Shadow Places: Patterns of Spatial Concentration and Incorporation of Irregular Immigrants in the Netherlands

Summary: In Western countries, irregular immigrants constitute a sizeable segment of the population. By combining quantitative and qualitative research methods, this article describes and explains irregular immigrants’ patterns of spatial concentration and incorporation in the Netherlands. So far these spatial patterns have not been described and explained systematically, neither in the Netherlands nor elsewhere. The article shows that illegal residence is selectively embedded in the (urban) social structure in various ways. The authors argue that irregular immigrants are likely to be spatially concentrated and incorporated in similar ways in other Western countries; now and in the foreseeable future

LLM3D: a log-linear modeling-based method to predict functional gene regulatory interactions from genome-wide expression data

All cellular processes are regulated by condition-specific and time-dependent interactions between transcription factors and their target genes. While in simple organisms, e.g. bacteria and yeast, a large amount of experimental data is available to support functional transcription regulatory interactions, in mammalian systems reconstruction of gene regulatory networks still heavily depends on the accurate prediction of transcription factor binding sites. Here, we present a new method, log-linear modeling of 3D contingency tables (LLM3D), to predict functional transcription factor binding sites. LLM3D combines gene expression data, gene ontology annotation and computationally predicted transcription factor binding sites in a single statistical analysis, and offers a methodological improvement over existing enrichment-based methods. We show that LLM3D successfully identifies novel transcriptional regulators of the yeast metabolic cycle, and correctly predicts key regulators of mouse embryonic stem cell self-renewal more accurately than existing enrichment-based methods. Moreover, in a clinically relevant in vivo injury model of mammalian neurons, LLM3D identified peroxisome proliferator-activated receptor γ (PPARγ) as a neuron-intrinsic transcriptional regulator of regenerative axon growth. In conclusion, LLM3D provides a significant improvement over existing methods in predicting functional transcription regulatory interactions in the absence of experimental transcription factor binding data

Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery

ObjectiveAntiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery. MethodsWe collected IQ scores of children from the TTS cohort with both pre- and postoperative neuropsychological assessments (NPAs; n=301) and analyzed whether reduction of AEDs prior to the latest NPA was related to postoperative IQ and delta IQ, using linear regression analyses. Factors previously identified as independently relating to (delta) IQ, and currently identified predictors of (delta) IQ, were considered possible confounders and used for adjustment. Additionally, we adjusted for a compound propensity score that contained previously identified determinants of timing of AED withdrawal. ResultsMean interval to the latest NPA was 19.818.9 months. Reduction of AEDs at the latest NPA significantly improved postoperative IQ and delta IQ (adjusted regression coefficient [RC]=3.4, 95% confidence interval [CI]=0.6-6.2, p=0.018 and RC=4.5, 95% CI=1.7-7.4, p=0.002), as did complete withdrawal (RC=4.8, 95% CI=1.4-8.3, p=0.006 and RC=5.1, 95% CI=1.5-8.7, p=0.006). AED reduction also predicted 10-point IQ increase (p=0.019). The higher the number of AEDs reduced, the higher was the IQ (gain) after surgery (RC=2.2, 95% CI=0.6-3.7, p=0.007 and RC=2.6, 95% CI=1.0-4.2, p=0.001, IQ points per AED reduced). InterpretationStart of AED withdrawal, number of AEDs reduced, and complete AED withdrawal were associated with improved postoperative IQ scores and gain in IQ, independent of other determinants of cognitive outcome. Ann Neurol 2015;78:104-11

Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used <i>Ercc1</i> mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged <i>Ercc1</i> mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and <i>Ercc1</i> mutant hippocampal neurons displayed normal outgrowth and synapse formation <i>in vitro</i>. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline

Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used <i>Ercc1</i> mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged <i>Ercc1</i> mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and <i>Ercc1</i> mutant hippocampal neurons displayed normal outgrowth and synapse formation <i>in vitro</i>. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline

Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used <i>Ercc1</i> mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged <i>Ercc1</i> mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and <i>Ercc1</i> mutant hippocampal neurons displayed normal outgrowth and synapse formation <i>in vitro</i>. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline

Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used <i>Ercc1</i> mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged <i>Ercc1</i> mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and <i>Ercc1</i> mutant hippocampal neurons displayed normal outgrowth and synapse formation <i>in vitro</i>. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline

Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used <i>Ercc1</i> mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged <i>Ercc1</i> mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and <i>Ercc1</i> mutant hippocampal neurons displayed normal outgrowth and synapse formation <i>in vitro</i>. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline

Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used <i>Ercc1</i> mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged <i>Ercc1</i> mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and <i>Ercc1</i> mutant hippocampal neurons displayed normal outgrowth and synapse formation <i>in vitro</i>. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline