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Artikeln behandlar ett återkommande språkligt mönster i idrottstränares instruktioner och återkoppling till tränande barn. Mönstret utgörs av ett tvåledat yttrande där ett instruerande led föregås av ett orienterande led med lägre informationsvärde och en delvis annan funktion. I artikeln beskrivs detta orienterande led som scene-setting, vilket syftar på att den orientering som föregår och förbereder instruktionen är nödvändig för att yttrandet i sin helhet ska fungera kommunikativt. Förekomsten av scene-setting i tränares instruktioner får konsekvenser för hur yttrandet struktureras språkligt, och i artikeln åskådliggörs detta genom analyser av två strukturer: dels en V3-struktur där en initial när-sats följs av en sats med rak ordföljd, dels en kontrasterande satsrelation som påverkar möjligheten att använda konjunktion. En central slutsats är att instruktionernas utformning är starkt påverkad av de speciella kommunikativa villkor som präglar en träningskontext som inkluderar barn.

Artikeln behandlar ett återkommande språkligt mönster i idrottstränares instruktioner och återkoppling till tränande barn. Mönstret utgörs av ett tvåledat yttrande där ett instruerande led föregås av ett orienterande led med lägre informationsvärde och en delvis annan funktion. I artikeln beskrivs detta orienterande led som scene-setting, vilket syftar på att den orientering som föregår och förbereder instruktionen är nödvändig för att yttrandet i sin helhet ska fungera kommunikativt. Förekomsten av scene-setting i tränares instruktioner får konsekvenser för hur yttrandet struktureras språkligt, och i artikeln åskådliggörs detta genom analyser av två strukturer: dels en V3-struktur där en initial när-sats följs av en sats med rak ordföljd, dels en kontrasterande satsrelation som påverkar möjligheten att använda konjunktion. En central slutsats är att instruktionernas utformning är starkt påverkad av de speciella kommunikativa villkor som präglar en träningskontext som inkluderar barn.

Artikeln behandlar ett återkommande språkligt mönster i idrottstränares instruktioner och återkoppling till tränande barn. Mönstret utgörs av ett tvåledat yttrande där ett instruerande led föregås av ett orienterande led med lägre informationsvärde och en delvis annan funktion. I artikeln beskrivs detta orienterande led som scene-setting, vilket syftar på att den orientering som föregår och förbereder instruktionen är nödvändig för att yttrandet i sin helhet ska fungera kommunikativt. Förekomsten av scene-setting i tränares instruktioner får konsekvenser för hur yttrandet struktureras språkligt, och i artikeln åskådliggörs detta genom analyser av två strukturer: dels en V3-struktur där en initial när-sats följs av en sats med rak ordföljd, dels en kontrasterande satsrelation som påverkar möjligheten att använda konjunktion. En central slutsats är att instruktionernas utformning är starkt påverkad av de speciella kommunikativa villkor som präglar en träningskontext som inkluderar barn.

Artikeln behandlar ett återkommande språkligt mönster i idrottstränares instruktioner och återkoppling till tränande barn. Mönstret utgörs av ett tvåledat yttrande där ett instruerande led föregås av ett orienterande led med lägre informationsvärde och en delvis annan funktion. I artikeln beskrivs detta orienterande led som scene-setting, vilket syftar på att den orientering som föregår och förbereder instruktionen är nödvändig för att yttrandet i sin helhet ska fungera kommunikativt. Förekomsten av scene-setting i tränares instruktioner får konsekvenser för hur yttrandet struktureras språkligt, och i artikeln åskådliggörs detta genom analyser av två strukturer: dels en V3-struktur där en initial när-sats följs av en sats med rak ordföljd, dels en kontrasterande satsrelation som påverkar möjligheten att använda konjunktion. En central slutsats är att instruktionernas utformning är starkt påverkad av de speciella kommunikativa villkor som präglar en träningskontext som inkluderar barn.

Artikeln behandlar ett återkommande språkligt mönster i idrottstränares instruktioner och återkoppling till tränande barn. Mönstret utgörs av ett tvåledat yttrande där ett instruerande led föregås av ett orienterande led med lägre informationsvärde och en delvis annan funktion. I artikeln beskrivs detta orienterande led som scene-setting, vilket syftar på att den orientering som föregår och förbereder instruktionen är nödvändig för att yttrandet i sin helhet ska fungera kommunikativt. Förekomsten av scene-setting i tränares instruktioner får konsekvenser för hur yttrandet struktureras språkligt, och i artikeln åskådliggörs detta genom analyser av två strukturer: dels en V3-struktur där en initial när-sats följs av en sats med rak ordföljd, dels en kontrasterande satsrelation som påverkar möjligheten att använda konjunktion. En central slutsats är att instruktionernas utformning är starkt påverkad av de speciella kommunikativa villkor som präglar en träningskontext som inkluderar barn.

Artikeln behandlar ett återkommande språkligt mönster i idrottstränares instruktioner och återkoppling till tränande barn. Mönstret utgörs av ett tvåledat yttrande där ett instruerande led föregås av ett orienterande led med lägre informationsvärde och en delvis annan funktion. I artikeln beskrivs detta orienterande led som scene-setting, vilket syftar på att den orientering som föregår och förbereder instruktionen är nödvändig för att yttrandet i sin helhet ska fungera kommunikativt. Förekomsten av scene-setting i tränares instruktioner får konsekvenser för hur yttrandet struktureras språkligt, och i artikeln åskådliggörs detta genom analyser av två strukturer: dels en V3-struktur där en initial när-sats följs av en sats med rak ordföljd, dels en kontrasterande satsrelation som påverkar möjligheten att använda konjunktion. En central slutsats är att instruktionernas utformning är starkt påverkad av de speciella kommunikativa villkor som präglar en träningskontext som inkluderar barn.

Für das Deutsche wird gemeinhin eine strikte V2-Beschränkung angenommen, die für deklarative Hauptsätze besagt, dass sich vor dem finiten Verb genau eine Konstituente befinden muss. In der Literatur werden häufig Beispiele angeführt, in denen sich zwei Konstituenten vor dem finiten Verb befinden und die somit gegen die V2-Beschränkung verstoßen. Diese syntaktische Konfiguration, so das Argument, führt zu Ungrammatikalität: (1) *Gestern Johann hat getanzt. (Roberts & Roussou 2002:137) Die Bewertung in (1) fußt jedoch nicht auf empirischer Evidenz, sondern spiegelt ein introspektives Urteil der Autor*innen wider. Daten zum tatsächlichen Sprachgebrauch zeigen, dass Sätze wie in (2) im Deutschen durchaus verwendet werden: (2) Aber immer alle sagen das. [BSa-OB, #16] Die Dissertation beschäftigt sich mit dem Status dieser V3-Deklarativsätze im Deutschen. Der Status wird aus drei einander ergänzenden Perspektiven auf Sprache untersucht: Sprachverwendung, Akzeptabilität und Verarbeitung. Hierzu werden Daten, die in einer Korpus-, einer Akzeptabilitäts- und einer Lesezeitstudie erhoben wurden, ausgewertet. Basierend auf den empirischen Befunden diskutiere ich V3-Modellierungen aus generativer Sicht und entwickle einen Modellierungsvorschlag aus konstruktionsgrammatischer Sicht. Die Arbeit zeigt, dass die Einbeziehung von nicht-standardsprachlichen Mustern wichtige Einblicke in die sprachliche Architektur gibt. Insbesondere psycholinguistisch gewonnene Daten als empirische Basis sind essenziell, um mentale sprachliche Prozesse zu verstehen und abbilden zu können. Die Analyse von V3 zeigt, dass solche Ansätze möglich und nötig sind, um Grammatikmodelle zu prüfen und weiterzuentwickeln. Untersuchungen dieser Art stellen Grammatikmodelle in Frage, die oft einer standardsprachlichen Tradition heraus erwachsen sind und nur einen Ausschnitt der sprachlichen Realität erfassen. V3-Sätze entpuppen sich nach dieser Analyse als Strukturen, die fester Bestandteil der Grammatik sind., German is usually considered to follow a strict V2-constraint. This means that exactly one constituent must precede the finite verb in declarative main clauses. There are many examples for sentences that exhibit two preverbal constituents in the literature, illustrating a violation of the V2-constraint. According to the literature, these configurations lead to ungrammatical structures. (1) *Gestern Johann hat getanzt. (Roberts & Roussou 2002:137) However, the evaluation in (1) is not based on empirical evidence but is introspective and thus might not reflect the linguistic reality. Empirical data from actual language use show that German speakers indeed use these kinds of sentences. (2) Aber immer alle sagen das. [BSa-OB, #16] The dissertation explores the status of these V3 declaratives in German, with ‘status’ comprising three complementary perspectives on language: language use, acceptability, and processing. To this end, I analyze data from three studies: a corpus study, an acceptability judgment study, and a reading time study. Based on the empirical evidence, I discuss existing analyses of V3 and V3-modeling from the generative perspective and develop an analysis taking a construction-based approach. The dissertation shows that including patterns from non-standard language allows for valuable insights into the architecture of language. In particular, psycholinguistic data as an empirical basis are essential to understand and model mental linguistic processes. The analyses presented in the dissertation show that it is possible to follow such an approach in the field of syntactic variation, and it is indeed necessary in order to challenge and further develop existing grammatical theories and our understanding of grammar. Most grammatical models strongly rely on standard language, which is why they only capture a snippet of the linguistic reality. Taking empirical evidence into account, however, V3 sentences turn out to form an integral part of the German grammar

Für das Deutsche wird gemeinhin eine strikte V2-Beschränkung angenommen, die für deklarative Hauptsätze besagt, dass sich vor dem finiten Verb genau eine Konstituente befinden muss. In der Literatur werden häufig Beispiele angeführt, in denen sich zwei Konstituenten vor dem finiten Verb befinden und die somit gegen die V2-Beschränkung verstoßen. Diese syntaktische Konfiguration, so das Argument, führt zu Ungrammatikalität: (1) *Gestern Johann hat getanzt. (Roberts & Roussou 2002:137) Die Bewertung in (1) fußt jedoch nicht auf empirischer Evidenz, sondern spiegelt ein introspektives Urteil der Autor*innen wider. Daten zum tatsächlichen Sprachgebrauch zeigen, dass Sätze wie in (2) im Deutschen durchaus verwendet werden: (2) Aber immer alle sagen das. [BSa-OB, #16] Die Dissertation beschäftigt sich mit dem Status dieser V3-Deklarativsätze im Deutschen. Der Status wird aus drei einander ergänzenden Perspektiven auf Sprache untersucht: Sprachverwendung, Akzeptabilität und Verarbeitung. Hierzu werden Daten, die in einer Korpus-, einer Akzeptabilitäts- und einer Lesezeitstudie erhoben wurden, ausgewertet. Basierend auf den empirischen Befunden diskutiere ich V3-Modellierungen aus generativer Sicht und entwickle einen Modellierungsvorschlag aus konstruktionsgrammatischer Sicht. Die Arbeit zeigt, dass die Einbeziehung von nicht-standardsprachlichen Mustern wichtige Einblicke in die sprachliche Architektur gibt. Insbesondere psycholinguistisch gewonnene Daten als empirische Basis sind essenziell, um mentale sprachliche Prozesse zu verstehen und abbilden zu können. Die Analyse von V3 zeigt, dass solche Ansätze möglich und nötig sind, um Grammatikmodelle zu prüfen und weiterzuentwickeln. Untersuchungen dieser Art stellen Grammatikmodelle in Frage, die oft einer standardsprachlichen Tradition heraus erwachsen sind und nur einen Ausschnitt der sprachlichen Realität erfassen. V3-Sätze entpuppen sich nach dieser Analyse als Strukturen, die fester Bestandteil der Grammatik sind., German is usually considered to follow a strict V2-constraint. This means that exactly one constituent must precede the finite verb in declarative main clauses. There are many examples for sentences that exhibit two preverbal constituents in the literature, illustrating a violation of the V2-constraint. According to the literature, these configurations lead to ungrammatical structures. (1) *Gestern Johann hat getanzt. (Roberts & Roussou 2002:137) However, the evaluation in (1) is not based on empirical evidence but is introspective and thus might not reflect the linguistic reality. Empirical data from actual language use show that German speakers indeed use these kinds of sentences. (2) Aber immer alle sagen das. [BSa-OB, #16] The dissertation explores the status of these V3 declaratives in German, with ‘status’ comprising three complementary perspectives on language: language use, acceptability, and processing. To this end, I analyze data from three studies: a corpus study, an acceptability judgment study, and a reading time study. Based on the empirical evidence, I discuss existing analyses of V3 and V3-modeling from the generative perspective and develop an analysis taking a construction-based approach. The dissertation shows that including patterns from non-standard language allows for valuable insights into the architecture of language. In particular, psycholinguistic data as an empirical basis are essential to understand and model mental linguistic processes. The analyses presented in the dissertation show that it is possible to follow such an approach in the field of syntactic variation, and it is indeed necessary in order to challenge and further develop existing grammatical theories and our understanding of grammar. Most grammatical models strongly rely on standard language, which is why they only capture a snippet of the linguistic reality. Taking empirical evidence into account, however, V3 sentences turn out to form an integral part of the German grammar

Charge injection and generation mechanisms under intense electric fields (up to 10(9)Vm(-1)) in mineral oil are assessed experimentally and numerically. For this, current-voltage characteristics under positive and negative polarities are measured in a needle-plane configuration using sharp needles (with tip radius R-tip <= 1.1 mu m). In addition, a state of the art electro-hydrodynamic (EHD) model is implemented to calculate the contribution of the different mechanisms on the high-field conduction currents in the liquid. In order to evaluate exclusively the contribution of field emission, experiments are also performed in vacuum. It is found that neither field emission nor field ionisation can explain the conduction currents measured in mineral oil. It is proposed that field molecular ionisation, as described by Zener tunnelling model for solids, and electron impact ionisation are the processes dominating the generation of excess electron-ion pairs in mineral oil under positive and negative polarity, respectively. It is also shown that Zener molecular ionisation alone grossly overestimates the measured currents when parameters previously suggested in the literature for mineral oil are used. Preliminary model parameters for these mechanisms that best fit the conduction currents measured in mineral oil are presented and discussed., QC 20190423

Protein subcellular localization is tightly controlled and intimately linked to protein function in health and disease. Capturing the spatial proteome - that is, the localizations of proteins and their dynamics at the subcellular level - is therefore essential for a complete understanding of cell biology. Owing to substantial advances in microscopy, mass spectrometry and machine learning applications for data analysis, the field is now mature for proteome-wide investigations of spatial cellular regulation. Studies of the human proteome have begun to reveal a complex architecture, including single-cell variations, dynamic protein translocations, changing interaction networks and proteins localizing to multiple compartments. Furthermore, several studies have successfully harnessed the power of comparative spatial proteomics as a discovery tool to unravel disease mechanisms. We are at the beginning of an era in which spatial proteomics finally integrates with cell biology and medical research, thereby paving the way for unbiased systems-level insights into cellular processes. Here, we discuss current methods for spatial proteomics using imaging or mass spectrometry and specifically highlight global comparative applications. The aim of this Review is to survey the state of the field and also to encourage more cell biologists to apply spatial proteomics approaches., QC 20190603

The temperature-dependent intrinsic stacking fault Gibbs energy is computed based on highly converged density-functional-theory (DFT) calculations for the three prototype face-centered cubic metals Al, Cu, and Ni. All relevant temperature-dependent contributions are considered including electronic, vibrational, magnetic, and explicit anharmonic Gibbs energy contributions as well as coupling terms employing state-of-the-art statistical sampling techniques. Particular emphasis is put on a careful comparison of different theoretical concepts to derive the stacking fault energy such as the axial-next-nearest-neighbor-Ising (ANNNI) model or the vacuum-slab approach. Our theoretical results are compared with an extensive set of previous theoretical and experimental data. Large uncertainties in the experimental data highlight the necessity of complementary parameter-free calculations. Specifically, the temperature dependence is experimentally unknown and poorly described by thermodynamic databases. Whereas CALPHAD derived data shows an increase of the stacking fault energy with temperature for two of the systems (Cu and Ni), our results predict a decrease for all studied systems. For Ni, the temperature induced change is in fact so strong that in the temperature interval relevant for super-alloy applications the stacking fault energy falls below one third of the low temperature value. Such large changes clearly call for a revision of the stacking fault energy when modeling or designing alloys based on such elements., QC 20220405

An implementation of the iterative proportional fitting (IPFP), maximum likelihood, minimum chi-square and weighted least squares procedures for updating a N-dimensional array with respect to given target marginal distributions (which, in turn can be multi-dimensional). The package also provides an application of the IPFP to simulate multivariate Bernoulli distributions.

An implementation of the iterative proportional fitting (IPFP), maximum likelihood, minimum chi-square and weighted least squares procedures for updating a N-dimensional array with respect to given target marginal distributions (which, in turn can be multi-dimensional). The package also provides an application of the IPFP to simulate multivariate Bernoulli distributions.

An implementation of the iterative proportional fitting (IPFP), maximum likelihood, minimum chi-square and weighted least squares procedures for updating a N-dimensional array with respect to given target marginal distributions (which, in turn can be multi-dimensional). The package also provides an application of the IPFP to simulate multivariate Bernoulli distributions.

An implementation of the iterative proportional fitting (IPFP), maximum likelihood, minimum chi-square and weighted least squares procedures for updating a N-dimensional array with respect to given target marginal distributions (which, in turn can be multi-dimensional). The package also provides an application of the IPFP to simulate multivariate Bernoulli distributions.

Objectives: Maraviroc has been shown to be effective in patients harbouring CCR5-tropic HIV-1. While this CCR5 antagonist has initially been used in salvage therapy, its excellent safety profile makes it ideal for antiretroviral treatment simplification strategies in patients with suppressed plasma viraemia. The aim of this study was to compare HIV-1 tropism as detected in baseline plasma RNA and peripheral blood mononuclear cell (PBMC) DNA prior to first-line therapy and to analyse tropism evolution while on successful treatment. Methods: HIV-1 tropism was determined using triplicate genotypic testing combined with geno2pheno[coreceptor] analysis at a 10% false positive rate in 42 patients. Paired pre-treatment plasma RNA and PBMC DNA and two subsequent PBMC DNA samples (the first obtained after reaching undetectable plasma HIV-1 RNA and the second after at least 2 years of suppression of plasma viraemia) were evaluated. Results: Coreceptor tropism was completely concordant in paired pre-treatment RNA and DNA, with 26.2% of HIV-1 sequences predicted to be non-CCR5-tropic. During follow-up, coreceptor tropism switches were detected in 4 (9.5%) patients without any preferential direction. Although false positive rate discrepancies within triplicates were common, the rate of discordance of coreceptor tropism assignment among triplicate results in this mostly CCR5-tropic dataset was only 2.1%, questioning the added value of triplicate testing compared with single testing. Conclusions: HIV-1 coreceptor tropism changes during virologically successful first-line treatment are infrequent. HIV-1 DNA analysis may thus support the choice of a CCR5 antagonist in treatment switch strategies; however, maraviroc treatment outcome data are required to confirm this option. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved

Accurate co-receptor tropism (CRT) determination is critical for making treatment decisions in HIV management. We created a genotypic tropism prediction tool by utilizing the case-based reasoning (CBR) technique that attempts to solve new problems through applying the solution from similar past problems. V3 loop sequences from 732 clinical samples with diverse characteristics were used to build a case library. Additional sequence and molecular properties of the V3 loop were examined and used for similarity assessment. A similarity metric was defined based on each attribute's frequency in the CXCR4-using viruses. We implemented three other genotype-based tropism predictors, support vector machines (SVM), position specific scoring matrices (PSSM), and the 11/25 rule, and evaluated their performance as the ability to predict CRT compared to Monogram's enhanced sensitivity Trofile(®) assay (ESTA). Overall concordance of the CBR based tropism prediction algorithm was 81%, as compared to ESTA. Sensitivity to detect CXCR4 usage was 90% and specificity was at 73%. In comparison, sensitivity of the SVM, PSSM, and the 11/25 rule were 85%, 81%, and 36% respectively while achieving a specificity of 90% by SVM, 75% by PSSM, and 97% by the 11/25 rule. When we evaluated these predictors in an unseen dataset, higher sensitivity was achieved by the CBR algorithm (87%), compared to SVM (82%), PSSM (76%), and the 11/25 rule (33%), while maintaining similar level of specificity. Overall this study suggests that CBR can be utilized as a genotypic tropism prediction tool, and can achieve improved performance in independent datasets compared to model or rule based methods.

Accurate co-receptor tropism (CRT) determination is critical for making treatment decisions in HIV management. We created a genotypic tropism prediction tool by utilizing the case-based reasoning (CBR) technique that attempts to solve new problems through applying the solution from similar past problems. V3 loop sequences from 732 clinical samples with diverse characteristics were used to build a case library. Additional sequence and molecular properties of the V3 loop were examined and used for similarity assessment. A similarity metric was defined based on each attribute's frequency in the CXCR4-using viruses. We implemented three other genotype-based tropism predictors, support vector machines (SVM), position specific scoring matrices (PSSM), and the 11/25 rule, and evaluated their performance as the ability to predict CRT compared to Monogram's enhanced sensitivity Trofile(®) assay (ESTA). Overall concordance of the CBR based tropism prediction algorithm was 81%, as compared to ESTA. Sensitivity to detect CXCR4 usage was 90% and specificity was at 73%. In comparison, sensitivity of the SVM, PSSM, and the 11/25 rule were 85%, 81%, and 36% respectively while achieving a specificity of 90% by SVM, 75% by PSSM, and 97% by the 11/25 rule. When we evaluated these predictors in an unseen dataset, higher sensitivity was achieved by the CBR algorithm (87%), compared to SVM (82%), PSSM (76%), and the 11/25 rule (33%), while maintaining similar level of specificity. Overall this study suggests that CBR can be utilized as a genotypic tropism prediction tool, and can achieve improved performance in independent datasets compared to model or rule based methods.

Maraviroc has been shown to be effective in patients harbouring CCR5-tropic HIV-1. While this CCR5 antagonist has initially been used in salvage therapy, its excellent safety profile makes it ideal for antiretroviral treatment simplification strategies in patients with suppressed plasma viraemia. The aim of this study was to compare HIV-1 tropism as detected in baseline plasma RNA and peripheral blood mononuclear cell (PBMC) DNA prior to first-line therapy and to analyse tropism evolution while on successful treatment.

Neuronal networks are the central functional units of the nervous system. Knowledge about the identity of participating neurons and the assembly of these during development is crucial for the understanding of CNS function. A promising system to dissect the development and functionalities of a neuronal network is the central pattern generator (CPG) for locomotion. We used screening approaches to identify spinal neuronal subpopulations by their specific gene expression, potentially involved in CPG function. Amongst others we found paired-like homeodomain transcription factor 2 (Pitx2) as a cholinergic interneuron marker for partition cells, with a possible role in the spinal network for locomotion. In addition, we present two genes, Chondrolectin (Chodl) and Estrogen-related receptor beta (ERRβ) as novel markers for fast and slow motor neurons, respectively. The neuronal components of the CPG integrate three key functions; rhythm generation, ipsilateral flexors/extensors coordination and bilateral coordination over the midline. Commissural interneurons (CINs) are considered to participate in the latter. During development axons are guided to their targets by the help of axon guidance molecules. Netrin-1 and its receptor DCC (Deleted in Colorectal Cancer) have been shown to play an important role for spinal cord neurons in axon-pathfinding and migration towards the midline. We show that loss of netrin-1 functionally results in a switch from alternating to synchronous left-right locomotor activity and deletion of DCC surprisingly leads to a different phenotype, best described as uncoordination. Thus, during development, netrin-1 and DCC play a critical role for the establishment of a functional balanced CPG. Further we show a selective loss of CINs, predominantly from dorsally originating subtypes, not affecting the ventral-most V3 subtype in netrin-1 mutant mice, but a loss of CINs from all progenitor domains in Dcc mutant mice. Together, our data suggest a netrin-1-in

Neuronal networks are the central functional units of the nervous system. Knowledge about the identity of participating neurons and the assembly of these during development is crucial for the understanding of CNS function. A promising system to dissect the development and functionalities of a neuronal network is the central pattern generator (CPG) for locomotion. We used screening approaches to identify spinal neuronal subpopulations by their specific gene expression, potentially involved in CPG function. Amongst others we found paired-like homeodomain transcription factor 2 (Pitx2) as a cholinergic interneuron marker for partition cells, with a possible role in the spinal network for locomotion. In addition, we present two genes, Chondrolectin (Chodl) and Estrogen-related receptor beta (ERRβ) as novel markers for fast and slow motor neurons, respectively. The neuronal components of the CPG integrate three key functions; rhythm generation, ipsilateral flexors/extensors coordination and bilateral coordination over the midline. Commissural interneurons (CINs) are considered to participate in the latter. During development axons are guided to their targets by the help of axon guidance molecules. Netrin-1 and its receptor DCC (Deleted in Colorectal Cancer) have been shown to play an important role for spinal cord neurons in axon-pathfinding and migration towards the midline. We show that loss of netrin-1 functionally results in a switch from alternating to synchronous left-right locomotor activity and deletion of DCC surprisingly leads to a different phenotype, best described as uncoordination. Thus, during development, netrin-1 and DCC play a critical role for the establishment of a functional balanced CPG. Further we show a selective loss of CINs, predominantly from dorsally originating subtypes, not affecting the ventral-most V3 subtype in netrin-1 mutant mice, but a loss of CINs from all progenitor domains in Dcc mutant mice. Together, our data suggest a netrin-1-in

RIVM rapport:Doel van het onderzoek was om inzicht te verkrijgen in de antigene en genetische variatie van het in Nederland en Curacao circulerende humane immunodeficientie virus type 1 (HIV-1). De genetische variatie tussen HIV-1 isolaten is aanzienlijk. De genetische variatie doet zich vooral voor op een vijftal gebieden van het deel van het virale genoom, dat codeert voor het externe envelop eiwit gp120 van HIV-1. Van deze vijf gebieden is het derde variabele domein (V3) gelegen tussen aminozuur-positities 269 en 331 van gp120 het meest uitvoerig bestudeerd. Van de Nederlandse serummonsters reageerde 54.8% specifiek tegen een van de peptiden p108, p109 of p110, welke representatief zijn voor het genotype B. Voor wat betreft de monsters afkomstig uit Curacao werd een vergelijkbaar resultaat gevonden, met dit verschil dat ten opzichte van de Nederlandse monsters een relatief hoge frequentie van serum reactiviteit tegen p110 werd gevonden. Op grond van de serologische reactiviteit in het V3 gebied kan worden geconcludeerd dat in de periode 1988 - 1990 in Nederland en Curacao subtype B HIV-1 varianten het meest prevalent waren. De V3-loop reactiviteit bleek vergelijkbaar met die gemeten in de Amsterdamse cohortstudies onder homoseksuele mannen en druggebruikers. De resultaten van de specifieke antistofreactiviteit werd in het algemeen bevestigd door de resultaten van het V3 sequentie-onderzoek, maar subtiele sequentieverschillen tussen de V3 loop reactiviteit en circulerend viraal V3 werden in een aantal gevallen aangetoond. Aanbevolen wordt in 1995 een tweede survey uit te voeren, te meer daar inmiddels meer bekend is over verschillende subtypen van HIV-1 en recent het zogeheten subtype O is beschreven., To obtain insight into the variation of the HIV-1 V3 neutralization domain of variants circulating in the Netherlands, 126 Dutch, 70 Curacao and 45 African serum samples from HIV-1 infected individuals were screened for antibody reactivity to a set of 16 to 17 mer synthetic peptides, representing the central part of the V3-loop of gp120 of HIV-1 variants circulating in the US, Europe and Africa. These peptides were used in an ELISA and antibody reactivity to the peptides was compared to the actual amino acid sequence of viral RNA circulating in a subset of the same serum samples. In conclusion, we found a relatively high genetic and antigenic homogeneity of the V3 gene of HIV infections in the Netherlands and Curacao during the years 1988-1990. Antibody reactivity to synthetic V3 peptides, as well as sequence analysis confirmed the prevalence of B subtype HIV-1 among the Dutch and Curacaon samples and the prevalence of A/D subtypes among the Tanzanian samples. Screening of HIV-1 positive serum samples for genetic typing by using a set of well defined synthetic V3 peptides appeared to be feasible. In combination with molecular analysis (V3 sequencing and/or hetroduplex mobility assay) of this method can be applied to obtain insight in changes in genetic and antigenic variation of HIV-1 in a population: changes within subtype B HIV-1 variants, as well as introduction of other (new) HIV-1 variants can this be surveyed. This is of importance to obtain insight in the (molecular) epidemiology of HIV-1 as well as with respect to the development and the eventual use of an HIV-1 vaccine.

RIVM rapport:Doel van het onderzoek was om inzicht te verkrijgen in de antigene en genetische variatie van het in Nederland en Curacao circulerende humane immunodeficientie virus type 1 (HIV-1). De genetische variatie tussen HIV-1 isolaten is aanzienlijk. De genetische variatie doet zich vooral voor op een vijftal gebieden van het deel van het virale genoom, dat codeert voor het externe envelop eiwit gp120 van HIV-1. Van deze vijf gebieden is het derde variabele domein (V3) gelegen tussen aminozuur-positities 269 en 331 van gp120 het meest uitvoerig bestudeerd. Van de Nederlandse serummonsters reageerde 54.8% specifiek tegen een van de peptiden p108, p109 of p110, welke representatief zijn voor het genotype B. Voor wat betreft de monsters afkomstig uit Curacao werd een vergelijkbaar resultaat gevonden, met dit verschil dat ten opzichte van de Nederlandse monsters een relatief hoge frequentie van serum reactiviteit tegen p110 werd gevonden. Op grond van de serologische reactiviteit in het V3 gebied kan worden geconcludeerd dat in de periode 1988 - 1990 in Nederland en Curacao subtype B HIV-1 varianten het meest prevalent waren. De V3-loop reactiviteit bleek vergelijkbaar met die gemeten in de Amsterdamse cohortstudies onder homoseksuele mannen en druggebruikers. De resultaten van de specifieke antistofreactiviteit werd in het algemeen bevestigd door de resultaten van het V3 sequentie-onderzoek, maar subtiele sequentieverschillen tussen de V3 loop reactiviteit en circulerend viraal V3 werden in een aantal gevallen aangetoond. Aanbevolen wordt in 1995 een tweede survey uit te voeren, te meer daar inmiddels meer bekend is over verschillende subtypen van HIV-1 en recent het zogeheten subtype O is beschreven., To obtain insight into the variation of the HIV-1 V3 neutralization domain of variants circulating in the Netherlands, 126 Dutch, 70 Curacao and 45 African serum samples from HIV-1 infected individuals were screened for antibody reactivity to a set of 16 to 17 mer synthetic peptides, representing the central part of the V3-loop of gp120 of HIV-1 variants circulating in the US, Europe and Africa. These peptides were used in an ELISA and antibody reactivity to the peptides was compared to the actual amino acid sequence of viral RNA circulating in a subset of the same serum samples. In conclusion, we found a relatively high genetic and antigenic homogeneity of the V3 gene of HIV infections in the Netherlands and Curacao during the years 1988-1990. Antibody reactivity to synthetic V3 peptides, as well as sequence analysis confirmed the prevalence of B subtype HIV-1 among the Dutch and Curacaon samples and the prevalence of A/D subtypes among the Tanzanian samples. Screening of HIV-1 positive serum samples for genetic typing by using a set of well defined synthetic V3 peptides appeared to be feasible. In combination with molecular analysis (V3 sequencing and/or hetroduplex mobility assay) of this method can be applied to obtain insight in changes in genetic and antigenic variation of HIV-1 in a population: changes within subtype B HIV-1 variants, as well as introduction of other (new) HIV-1 variants can this be surveyed. This is of importance to obtain insight in the (molecular) epidemiology of HIV-1 as well as with respect to the development and the eventual use of an HIV-1 vaccine.

RIVM rapport:Doel van het onderzoek was om inzicht te verkrijgen in de antigene en genetische variatie van het in Nederland en Curacao circulerende humane immunodeficientie virus type 1 (HIV-1). De genetische variatie tussen HIV-1 isolaten is aanzienlijk. De genetische variatie doet zich vooral voor op een vijftal gebieden van het deel van het virale genoom, dat codeert voor het externe envelop eiwit gp120 van HIV-1. Van deze vijf gebieden is het derde variabele domein (V3) gelegen tussen aminozuur-positities 269 en 331 van gp120 het meest uitvoerig bestudeerd. Van de Nederlandse serummonsters reageerde 54.8% specifiek tegen een van de peptiden p108, p109 of p110, welke representatief zijn voor het genotype B. Voor wat betreft de monsters afkomstig uit Curacao werd een vergelijkbaar resultaat gevonden, met dit verschil dat ten opzichte van de Nederlandse monsters een relatief hoge frequentie van serum reactiviteit tegen p110 werd gevonden. Op grond van de serologische reactiviteit in het V3 gebied kan worden geconcludeerd dat in de periode 1988 - 1990 in Nederland en Curacao subtype B HIV-1 varianten het meest prevalent waren. De V3-loop reactiviteit bleek vergelijkbaar met die gemeten in de Amsterdamse cohortstudies onder homoseksuele mannen en druggebruikers. De resultaten van de specifieke antistofreactiviteit werd in het algemeen bevestigd door de resultaten van het V3 sequentie-onderzoek, maar subtiele sequentieverschillen tussen de V3 loop reactiviteit en circulerend viraal V3 werden in een aantal gevallen aangetoond. Aanbevolen wordt in 1995 een tweede survey uit te voeren, te meer daar inmiddels meer bekend is over verschillende subtypen van HIV-1 en recent het zogeheten subtype O is beschreven., To obtain insight into the variation of the HIV-1 V3 neutralization domain of variants circulating in the Netherlands, 126 Dutch, 70 Curacao and 45 African serum samples from HIV-1 infected individuals were screened for antibody reactivity to a set of 16 to 17 mer synthetic peptides, representing the central part of the V3-loop of gp120 of HIV-1 variants circulating in the US, Europe and Africa. These peptides were used in an ELISA and antibody reactivity to the peptides was compared to the actual amino acid sequence of viral RNA circulating in a subset of the same serum samples. In conclusion, we found a relatively high genetic and antigenic homogeneity of the V3 gene of HIV infections in the Netherlands and Curacao during the years 1988-1990. Antibody reactivity to synthetic V3 peptides, as well as sequence analysis confirmed the prevalence of B subtype HIV-1 among the Dutch and Curacaon samples and the prevalence of A/D subtypes among the Tanzanian samples. Screening of HIV-1 positive serum samples for genetic typing by using a set of well defined synthetic V3 peptides appeared to be feasible. In combination with molecular analysis (V3 sequencing and/or hetroduplex mobility assay) of this method can be applied to obtain insight in changes in genetic and antigenic variation of HIV-1 in a population: changes within subtype B HIV-1 variants, as well as introduction of other (new) HIV-1 variants can this be surveyed. This is of importance to obtain insight in the (molecular) epidemiology of HIV-1 as well as with respect to the development and the eventual use of an HIV-1 vaccine.