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Resource Teachers: Learning and Behaviour (RTLB) work with teachers to identify learning and behaviour needs of students who experience barriers to educational success. The language RTLB use can have a significant impact on teachers’ response to the inclusion of students with special learning needs and is key to improving educational outcomes for all learners. We examined the extent to which RTLB in New Zealand used inclusive, strengths-based language in initial meetings with teachers and whether shifts could be made through professional learning and development (PLD). Data collected included audio recordings, transcripts of initial meetings pre- and post-PLD, RTLB reflections on both transcripts, and questionnaires. Results indicate limited use of inclusive, strengths-based language prior to PLD. However, PLD that provided targeted opportunities to reflect on evidence of language behaviour and to practise requisite skills markedly increased RTLB awareness, knowledge, and skills with respect to inclusive, strengths-based language. Findings indicate that change often requires disrupting long-held beliefs and practices and a need for evidence of these to be able to do so. The findings have implications for the type of in-depth PLD needed to facilitate change in the language RTLB use when working with teachers.

We report the results of a vignette study with an online sample of the German adult population in which we analyze the interplay between need, equity, and accountability in third-party distribution decisions. We asked participants to divide firewood between two hypothetical persons who either differ in their need for heat or in their productivity in terms of their ability to chop wood. The study systematically varies the persons’ accountability for their neediness as well as for their productivity. We find that participants distribute significantly fewer logs of wood to persons who are held accountable for their disadvantage. Independently of being held accountable or not, the needier person is partially compensated with a share of logs that exceeds her contribution, while the person who contributes less is given a share of logs smaller than her need share. Moreover, there is a domain effect in terms of participants being more sensitive to lower contributions than to greater need.

While the link between self-perceptions of aging (SPA) and healthy aging is well established, less is known about how SPA relate to social factors. The present study investigated whether higher social network diversity is associated with more gain-related SPA and less loss-related SPA and whether this association is moderated by chronological age. We examined data from the German Ageing Survey of 2008 (DEAS; N = 6,205, 40–85 years, 49.5% female). Network diversity was assessed as the number of social roles in an individual’s social network. Three dimensions of SPA were measured with the Aging-Related Cognitions Scale (AgeCog; ongoing development, social losses, physical losses). We conducted multiple linear regression models and tested for a moderator effect of chronological age using an interaction term of age and network diversity. Results showed that at higher ages older adults with higher network diversity reported more gain-related SPA in the dimension of ongoing development than those with less diverse networks, supporting a moderating effect of age. Loss-related SPA in the dimension of social losses showed a small positive association with network diversity while loss-oriented SPA in the dimension of physical losses did not appear to be related to network diversity. Age had no relevance for either relationship. The present study adds to evidence on the role of social relationships for SPA. Our findings suggest that in certain dimensions and partly depending on age, social network diversity is both related to more gain-related and more loss-related SPA.

Neighbourhood effects research has benefited from the application of sequence analysis which, together with cluster analysis, identifies the main temporal patterns of exposure to residential contexts experienced by different groups of people, such as children. However, given that this is a relatively new approach to measuring exposure to neighbourhood deprivation, studies that have utilised sequence analysis to model residential trajectories and test for neighbourhood effects do not contextualise these population-level findings at the individual-level. The current study sought to investigate the patterns of exposure to neighbourhood deprivation experienced by children in Aotearoa New Zealand over the first eight years of life by utilising two different methodological approaches: at the macro-level, the results of the sequence and cluster analysis suggest that in general, children experienced little neighbourhood mobility; at the micro-level, children experienced greater levels of movement between different levels of neighbourhood deprivation in middle childhood, compared to early childhood, while children in the least and most deprived neighbourhoods experienced less mobility than their peers. Together, these findings provide a comprehensive description of the ways in which children are exposed to different residential contexts over time and advance our understandings of how to document these experiences effectively within quantitative research.

This study sheds light on the relationship between cognition and patience by documenting that the correlation between cognitive abilities and delay discounting is weaker for the same group of individuals if choices are incentivized. This study conjectures that higher cognitive effort, which induces higher involvement of the cognitive system, moderates the relationship between patience and cognition. For 107 participants drawn from the adult population in Tbilisi, this study examines the relationship between various measures of cognitive ability and that of patience. Specifically, we consider the relationship between the Cognitive Reflection Test, a numeracy test, self-reported math ability measure, enumerators’ assessments, and incentivized and hypothetical trade-offs between smaller-sooner and larger-later payments.

Academic resilience captures academic success despite adversity and thus is an important concept for promoting equity within education. However, our understanding of how and why rates of academic resilience differ between contexts is currently limited by variation in the ways that the construct has been operationalised in quantitative research. Similarly, comparing the strength of protective factors that promote academic resilience is hindered by differing approaches to the measurement of academic resilience. This methodological variation has complicated attempts to reconcile disparate findings about academic resilience. The current study applied six commonly used operationalisations of academic resilience that combined different thresholds of high risk and high achievement, to three international large-scale assessments, to explore how these different operationalisations impacted the findings produced. The context of Aotearoa New Zealand was chosen as a case study to further academic resilience research within this context and investigate how academic resilience manifests in an education system with relatively high levels of average achievement alongside low levels of educational equity. Within international large-scale assessment datasets, prevalence rates differed markedly across subject areas, grade levels, and collection cycles, as a function of the measure of academic resilience employed, while the strength of protective factors was more consistent. Thresholds that were norm-referenced produced more consistent findings across the different datasets compared to thresholds that were criterion-referenced. High levels of missing data prevented the analysis of some datasets, and differences in the way that key constructs were measured undermined the comparability of findings across international large-scale assessments. The findings emphasise the strengths and limitations of utilising international large-scale assessment data for the study of academic resilience, particularly within the Aotearoa New Zealand context. Furthermore, the study highlights that researchers' methodological decisions have important impacts on the conclusions drawn about academic resilience.The online version contains supplementary material available at 10.1007/s11092-022-09384-0.

first_pagesettingsOrder Article ReprintsOpen AccessArticleDynamics and Heterogeneity of Environmental Attitude, Willingness and Behavior in Germany from 1993 to 2021by Frauke Meyer, Hawal Shamon* [ORCID] and Stefan Vögele[ORCID]Forschungszentrum Jülich GmbH, Institut für Energie- und Klimaforschung, Systemforschung und Technologische Entwicklung (IEK-STE), 52425 Jülich, Germany*Author to whom correspondence should be addressed.Sustainability 2022, 14(23), 16207; https://doi.org/10.3390/su142316207Received: 26 October 2022 / Revised: 23 November 2022 / Accepted: 24 November 2022 / Published: 5 December 2022(This article belongs to the Section Social Ecology and Sustainability)Download Browse FiguresVersions NotesAbstractThis paper analyzes environmental attitude, willingness, and behavior using a relatively broad range of survey items from the four Environment Modules of the International Social Survey Programme (ISSP) in Germany. The ISSP Environment Module is a repeated cross-sectional large-scale survey in Germany covering a period of nearly 30 years with four survey waves (1993, 2000, 2010, and 2020). We find that environmental attitude, willingness, and behavior are relatively stable between 1993 and 2010 in Germany. However, in the fourth wave, we find a significant upward trend in attitude and willingness compared to 2010—even though the COVID-19 pandemic was omnipresent at the time of the survey. This could indicate that climate change and environmental issues have gained such significance that they cannot easily be fully displaced by other major events, such as a pandemic. Moreover, we detect systematic heterogeneity in environmental attitude, willingness, and behavior predominantly with respect to respondents’ education, residential region, and political orientation but also some heterogeneity regarding gender, age, and income. Finally, we reveal that the dynamic of environmental attitude, willingness, and behavior also depends on certain socio-demographic characteristics, such as residential region, or political orientation. Our findings are essential for a better understanding of the social feasibility of transformation pathways towards a sustainable energy system.

The stability of extracellular matrices is in general ensured by cross-linking of its components. Previously, we had shown that the integrity of the layered Drosophila cuticle relies on the presence of a covalent cuticular dityrosine network. Production and composition of this structure remained unstudied. In this work, we present our analyses of the schlaff (slf) gene coding for a putative C-type lectin that is needed for the adhesion between the horizontal cuticle layers. The Slf protein mainly localizes between the two layers called epicuticle and procuticle that separate from each other when the function of Slf is reduced or eliminated paralleling the phenotype of a cuticle with reduced extracellular dityrosine. Localisation of the dityrosinylated protein Resilin to the epicuticle-procuticle interface suggests that the dityrosine network mediates the adhesion of the epicuticle to the procuticle. Ultimately, compromised Slf function is associated with massive water loss. In summary, we propose that Slf is implied in the stabilisation of a dityrosine layer especially between the epicuticle and the procuticle that in turn constitutes an outward barrier against uncontrolled water flow.

Teacher judgments of student achievement are increasingly used for high-stakes decision-making, making it imperative that judgments be as fair and reliable as possible. Using a large national database from New Zealand, we explored the relation between psychometrically designed standardized achievement results and teacher judgments in reading ( N = 4771 students) and writing ( N = 11,765 students) using hierarchical linear modelling. Our findings indicated that judgments were systematically lower for marginalized learners after controlling for standardized achievement differences. Additionally, classroom and school achievement composition were inversely related to teacher judgments. These discrepancies are concerning, with important implications for equitable educational opportunities.

INTRODUCTION: Medulloblastoma is the most common malignant brain tumor of childhood and is a genetically heterogeneous disease. Amongst all medulloblastoma subgroups, MYC-amplified medulloblastomas are associated with a particularly poor prognosis as they are commonly metastatic and resistant to standard therapy. However, MYC amplification is restricted to a cellular subpopulation within MYC-amplified tumors. The underlying mechanisms mediating this cellular heterogeneity remain poorly understood. HYPOTHESIS: We hypothesize that a secretome-dependent crosstalk between MYC-amplified and non-MYC-amplified cells shapes an intratumoral microenvironment that promotes medulloblastoma aggressiveness. METHODS AND RESULTS: We first demonstrate that MYC overexpressing (high-MYC) cells induce proliferation and invasive growth patterns in their isogenic counterparts with low MYC expression (low-MYC) using contacting and non-contacting co-culture systems in three different medulloblastoma cell lines (ONS76, DAOY and UW228-3). Secondly, we demonstrate that exosomes from high-MYC cells promote the migratory propensity of low-MYC cells in vitro. Importantly, we confirmed the pro-tumorigenic interaction of high-MYC and low-MYC cells using two orthotopic medulloblastoma xenograft models. We further demonstrate that low-MYC cells promote tumor angiogenesis in vivo. Using an unbiased proteomic discovery approach and targeted validation by Western blotting, we identified and verified secreted proteins that may mediate this interaction. Rescue experiments validated the relevance of these candidates using functional genomics approaches in vitro, with in vivo validation being currently ongoing. CONCLUSION: We demonstrate that the crosstalk between cellular subclones in MYC-driven medulloblastoma may promote tumor growth, metastasis and angiogenesis. Understanding the underlying secretory signaling networks may elucidate novel therapeutic vulnerabilities in this prognostically poor subgroup of medulloblastoma.

Leseprobe ----- Zusammenfassung Der Beitrag richtet den Blick anhand der Leitfrage, was transnationale Bildung in einem postkolonialen Kontext von Asyl und Exil bedeuten kann, auf die seltener thematisierten Formen von Transnationalitat. Zunachst wird das Konzept transnationaler Bildung um eine postkoloniale Perspektive erweitert und dann ein erweiterter Bildungsbegriff vorgeschlagen, der es erlaubt, die in- und nonformalen Bildungsprozesse, wie sie im Kontext von Flucht und Asyl haufig sind, zu erfassen. Anhand zweier Fallbeispiele wird schlieslich illustriert, was transnationale Bildung unter den postkolonialen Bedingungen des Asyls bzw. Exils bedeuten kann. Schlagworter: Transnationalitat, Fluchtmigration, Bildung “Businessmen are everywhere useful”. Or: “I’d simply like to retreat.” – What Transnational ----- Education could mean in a Postcolonial Context of Asylum and Exile Abstract The paper focusses the less discussed forms of transnationalty guided by the question what transnational education (Bildung) could mean in a postcolonial context of asylum and exile. First, the concept of transnational Bildung is broaden by a postcolonial perspective. Then, an extended concept of Bildung is proposed which allows integrating in- and nonformal processes of Bildung being often characteristic for asylum and exile contexts. Finally, two case studies illustrate what transnational education could mean under the postcolonial conditions of asylum and exile. Keywords: transnationality, flight migration, education (Bildung) ----- Bibliographie: Meyer, Frauke: „Kaufleute kann man uberall brauchen.“ Oder: „Ich will mich einfach zuruckziehen.“ – Was transnationale Bildung in postkolonialen Kontexten von Asyl und Exil bedeuten kann, Diskurs Kindheits- und Jugendforschung / Discourse. Journal of Childhood and Adolescence Research, 4-2019, S. 405-416. https://doi.org/10.3224/diskurs.v14i4.03

Summary The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

The stability of extracellular matrices is in general ensured by cross-linking of its components. Previously, we had shown that the integrity of the layeredDrosophilacuticle relies on the presence of a covalent cuticular dityrosine network. Production and composition of this structure remained unstudied. In this work, we present our analyses of theschlaff(slf) gene coding for a C-type lectin that is needed for the adhesion between the horizontal cuticle layers. The Slf protein mainly localizes between the two layers called epicuticle and procuticle that separate from each other when the function of Slf is reduced or eliminated paralleling the phenotype of a cuticle with reduced extracellular dityrosine. Localisation of the dityrosinylated protein Resilin to the epicuticle-procuticle interface suggests that the dityrosine network mediates the adhesion of the epicuticle to the procuticle. Ultimately, compromised Slf function is associated with massive water loss. In summary, we propose that Slf is implied in the stabilisation of a dityrosine layer especially between the epicuticle and the procuticle that in turn constitutes an outward barrier against uncontrolled water flow.Summary statementExtracellular matrices adopt a stereotypic organisation for function during development. The lectin Schlaff assists adhesion reactions to ensure compactness of the epidermal cuticle in Drosophila.

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Aberrant MAPK signaling, typically mediated by BRAF alterations, drives PA formation. While five-year overall survival rates exceed 95%, incompletely resected tumors recur frequently despite treatment. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach utilizes RNA sequencing and LC/MS-based proteomic profiling and Similarity Fusion Network (SNF) analysis reveals the biological heterogeneity of PA. Integrative genomics dissects aberrant pathway activation in biological subgroups. Lastly, we utilize a drug screening pipeline to evaluate selective therapeutic activity of conventional anti-cancer and phase III/IV clinical trial drugs in PA culture models. PAs segregate into three groups with distinct clinical and molecular features. Age and tumor location are significantly associated with the SNF groups. BRAF fusions were predominantly observed in Groups 1 and 2, while Group 3 PA largely harbored other alterations leading to MAPK activation. Pathway enrichment analyses reveals genesets involved in primary ciliogenesis in Group 3, while immune response signatures, many SYK-related, are associated with Group 1. Confirming this analysis, the SYK inhibitor R788 was specifically active in Group 1, and less active in other brain tumors models (n=27). In summary, our proteogenomic approach reveals important biological heterogeneity with novel therapeutic targets emerging in PA. These biological insights may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of progressive disease.

Pilocytic astrocytoma (PA) is a well-circumscribed, slow growing, low-grade brain tumor predominantly affecting children and considered a single-pathway disease with activation of MAPK signaling, typically driven by BRAF alterations. While five-year overall survival rates exceed 95%, incompletely resected tumors recur frequently despite radiation and/or chemotherapy. Less favorable responses to multimodal therapies are observed in adults compared to pediatric patients. Thus, we utilized a proteogenomics approach to discern the biological heterogeneity of PA across all age-groups to identify novel therapeutic targets. Our proteogenomic approach encompasses RNA sequencing (RNAseq) and LC/MS-based proteomic profiling in a cohort of pediatric (n=55) and adult cases (n=24). Unsupervised hierarchical clustering is used to determine the biological heterogeneity of the disease. Integrative genomics, combined with downstream pathway analysis, dissects aberrant pathway activation in biological subgroups. Lastly, we utilize a drug screening pipeline encompassing conventional chemotherapeutics and targeted therapeutics (n=211) currently evaluated in phase III and IV clinical trials to validate novel molecular targets in PA culture models (n=8). Pediatric and adult PA segregate into two subgroups identified by unsupervised hierarchical clustering using RNAseq and proteomic profiling (p=0.001). Adult tumors form a single entity, while we observed additional heterogeneity in pediatric tumors segregating into two subgroups (p=0.01). Initial analyses show that adult PA demonstrate an over-representation of genes involved in translation initiation and ciliogenesis according to GeneSet Enrichment Analysis, whereas pediatric PA show a significant enrichment of pathways involved in glycolysis, signal transmission and AKT signaling. In all, our proteogenomic approach reveals important biological heterogeneity in pediatric and adult PA. Ongoing drug profiling is used to determine therapeutics with preferential activity against pediatric and adult PA cultures compared to neural stem cells and astrocytes. These biological insights may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of progressive disease.

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Aberrant MAPK signaling, typically mediated by BRAF alterations, drives PA tumorigenesis. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapeutic approaches. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing, DNA methylation profiling and LC/MS-based proteomic profiling data from a cohort of 75 primary PA samples. Similarity Fusion Network (SNF) analysis was conducted to discern the biological heterogeneity of PA. Integrative genomics was used to identify aberrant pathway activation in these biological subgroups. Lastly, we utilized a drug screening pipeline to evaluate selective therapeutic activity of conventional anti-cancer and phase III/IV clinical trial drugs in PA culture models. Pilocytic astrocytomas segregate into two groups with distinct clinical and molecular features. Age is significantly associated with the SNF groups. BRAF fusions were predominantly observed in Group 1, while Group 2 PAs largely harbored other alterations leading to MAPK activation. Importantly, we could confirm these two distinct biological subgroups in two independent, non-overlapping cohorts. Pathway enrichment analyses reveal genesets involved in ion channel activity, neurotransmitter signaling and cellular respiration, whereas largely SYK-related immune response signatures are associated with Group 1. Confirming this analysis, the SYK inhibitor R788 was specifically active in Group 1 PAs, and less active in other brain tumor models (n=13).

BMP4 has been linked to early steps of adipocyte lineage differentiation but only little is known about its corresponding downstream pathways. Herein, we have investigated whether or not the expression of high mobility group protein HMGA2, another protein linked to proliferation and differentiation within the process of adipogenesis, may be influenced by BMP4 signaling in adipose tissue derived stem cells. Compared to FGF1, a strong inducer of HMGA2 in immortalized pre-adipocytes, BMP4 was found moderately to induce the HMGA2 mRNA expression in serum starved adipose tissue derived stem cells and myometrial cells. In contrast, no such activity was noted in canine bone marrow derived mesenchymal stem cells. As to adipocyte lineage differentiation the functions of BMP4 and HMGA2 mechanistically overlap. Thus, we propose that in adipose tissue BMP4 acts in part by activating HMGA2 making this architectural transcription factor one of the major downstream players in that system.

Multiplexins are multidomain collagens typically composed of an N-terminal thrombospondin-related domain, an interrupted triple helix and a C-terminal endostatin domain. They feature a clear regulatory function in the development of different tissues, which is chiefly conveyed by the endostatin domain. This domain can be found in proteolytically released monomeric and trimeric versions, and their diverse and opposed effects on the migratory behavior of epithelial and endothelial cell types have been demonstrated in cell culture experiments. The only Drosophila multiplexin displays specific features of both vertebrate multiplexins, collagens XV and XVIII. We characterized the Drosophila multiplexin (dmp) gene and found that three main isoforms are expressed from it, one of which is the monomeric endostatin version. Generation of dmp deletion alleles revealed that Dmp plays a role in motor axon pathfinding, as the mutants exhibit ventral bypass defects of the intersegmental nerve b (ISNb) similar to other motor axon guidance mutants. Transgenic overexpression of monomeric endostatin as well as of full-length Dmp, but not trimeric endostatin, were able to rescue these defects. In contrast, trimeric endostatin increased axon pathfinding accuracy in wild type background. We conclude that Dmp plays a modulating role in motor axon pathfinding and may be part of a buffering system that functions to avoid innervation errors.

Animals construct a layered skin to prevent dehydration and pathogen entrance. The barrier function of the skin relies on the extensive cross-linking of specialised components. In insects, for instance, epidermal cells produce an apical extracellular cuticle that consists of a network of proteins, chitin and lipids. We have identified mutations in the Drosophila gene coding for the δ-aminolevulinate synthase (Alas) that cause massive water loss. The cuticle of alas mutant larvae detaches from the epidermis and its basal region is frayed suggesting that an Alas dependent pathway is needed to organise the contact between the cuticle and the epidermis and anchor the cuticle to the apical surface of epidermal cells. Concomitantly, reduction of Alas function results in weakening of the extracellular dityrosines network in the cuticle, whereas glutamyl–lysine isopeptide bonds are not affected. The lateral septate junctions of epidermal cells that serve as a paracellular plug are intact, as well. Taken together, we hypothesise that Alas activity, which initiates heme biosynthesis in the mitochondrion, is needed for the formation of a dityrosine-based barrier that confers resistance to the internal hydrostatic pressure protecting both the cuticle from transcellular infiltration of body fluid and the animal from dehydration. We conclude that at least two modules – an apical protein–chitin lattice and the lateral septate junctions, act in parallel to ensure Drosophila skin impermeability.

Teratogenicity can be predicted in vitro using the embryonic stem cell test (EST). The EST, which is based on the morphometric measurement of cardiomyocyte differentiation and cytotoxicity parameters, represents a scientifically validated method for the detection and classification of chemicals according to their teratogenic potency. Furthermore, an abbreviated protocol applying flow cytometry of intracellular marker proteins to determine differentiation into the cardiomyocyte lineage is available. Although valproic acid (VPA) is in worldwide clinical use as antiepileptic drug, it exhibits two severe side effects, i.e., teratogenicity and hepatotoxicity. These limitations have led to extensive research into derivatives of VPA. Here we chose VPA as model compound to test the applicability domain and to further evaluate the reliability of the EST. To this end, we study six closely related congeners of VPA and demonstrate that both the standard and the molecular flow cytometry-based EST are well suited to indicate differences in the teratogenic potency among VPA analogs that differ only in chirality or side chain length. Our data show that identical results can be obtained by using the standard EST or a shortened protocol based on flow cytometry of intracellular marker proteins. Both in vitro protocols enable to reliably determine differentiation of murine stem cells toward the cardiomyocyte lineage and to assess its chemical-mediated inhibition.

Navigation of motoneuronal growth cones toward the somatic musculature in Drosophila serves as a model system to unravel the molecular mechanisms of axon guidance and target selection. In a large-scale mutagenesis screen, we identified piranha, a motor axon guidance mutant that shows strong defects in the neuromuscular connectivity pattern. In piranha mutant embryos, permanent defasciculation errors occur at specific choice points in all motor pathways. Positional cloning of piranha revealed point mutations in tolloid-related 1(tlr1), an evolutionarily conserved gene encoding a secreted metalloprotease. Ectopic expression of Tlr1 in several tissues of piranha mutants, including hemocytes, completely restores the wild-type innervation pattern, indicating that Tlr1 functions cell non-autonomously. We further show that loss-of-function mutants of related metalloproteases do not have motor axon guidance defects and that the respective proteins cannot functionally replace Tlr1. tlr1, however,interacts with sidestep, a muscle-derived attractant. Double mutant larvae of tlr1 and sidestep show an additive phenotype and lack almost all neuromuscular junctions on ventral muscles, suggesting that Tlr1 functions together with Sidestep in the defasciculation process.

1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses mediated through 5-HT1-like and 5-HT2A receptors, f1 and f2 = 1-f1, were estimated by use of the 5-HT2A-selective antagonist ketanserin. 2. In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) and -log EC50, M of 6.4 and f1 of 0.20 (1000 nM ketanserin). 3. In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and f1 of 0.14 (1000 nM ketanserin). 4. The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT1-like receptors. 5. In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6. In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000 nM. 7. We conclude that 80-86% of the maximum 5-HT-evoked contraction of human temporal artery is mediated through 5-HT2A receptors, the remainder through 5-HT1-like-receptors, regardless of whether or not endothelium is functional. The 5-HT1-like-receptors are more likely to be 5-HT1D beta receptors than 5-HT1D alpha receptors and sumatriptan is a full agonist for these receptors. As found in arteries of other species, SK&F 103829 is a partial agonist for 5-HT2A receptors of human temporal artery.