348 research outputs found

    Statistical inference of the generation probability of T-cell receptors from sequence repertoires

    Full text link
    Stochastic rearrangement of germline DNA by VDJ recombination is at the origin of immune system diversity. This process is implemented via a series of stochastic molecular events involving gene choices and random nucleotide insertions between, and deletions from, genes. We use large sequence repertoires of the variable CDR3 region of human CD4+ T-cell receptor beta chains to infer the statistical properties of these basic biochemical events. Since any given CDR3 sequence can be produced in multiple ways, the probability distribution of hidden recombination events cannot be inferred directly from the observed sequences; we therefore develop a maximum likelihood inference method to achieve this end. To separate the properties of the molecular rearrangement mechanism from the effects of selection, we focus on non-productive CDR3 sequences in T-cell DNA. We infer the joint distribution of the various generative events that occur when a new T-cell receptor gene is created. We find a rich picture of correlation (and absence thereof), providing insight into the molecular mechanisms involved. The generative event statistics are consistent between individuals, suggesting a universal biochemical process. Our distribution predicts the generation probability of any specific CDR3 sequence by the primitive recombination process, allowing us to quantify the potential diversity of the T-cell repertoire and to understand why some sequences are shared between individuals. We argue that the use of formal statistical inference methods, of the kind presented in this paper, will be essential for quantitative understanding of the generation and evolution of diversity in the adaptive immune system.Comment: 20 pages, including Appendi

    Captivated by thought:"Sticky" thinking leaves traces of perceptual decoupling in task-evoked pupil size

    Get PDF
    Throughout the day, we may sometimes catch ourselves in patterns of thought that we experience as rigid and difficult to disengage from. Such "sticky" thinking can be highly disruptive to ongoing tasks, and when it turns into rumination constitutes a vulnerability for mental disorders such as depression and anxiety. The main goal of the present study was to explore the stickiness dimension of thought, by investigating how stickiness is reflected in task performance and pupil size. To measure spontaneous thought processes, we asked participants to perform a sustained attention to response task (SART), in which we embedded the participant's concerns to potentially increase the probability of observing sticky thinking. The results indicated that sticky thinking was most frequently experienced when participants were disengaged from the task. Such episodes of sticky thought could be discriminated from neutral and non-sticky thought by an increase in errors on infrequent no-go trials. Furthermore, we found that sticky thought was associated with smaller pupil responses during correct responding. These results demonstrate that participants can report on the stickiness of their thought, and that stickiness can be investigated using pupillometry. In addition, the results suggest that sticky thought may limit attention and exertion of cognitive control to the task

    Concomitant endocarditis and spondylodiscitis due to coagulase-negative Staphylococci and a review of the literature

    Get PDF
    Background: Coagulase-negative staphylococci (CoNS) are part of the normal skin flora. Although CoNS are generally considered as low pathogenic microorganisms, they can cause serious infections, particularly in the context of foreign body material. Case report: Here we present two cases of concomitant infectious endocarditis and spondylodiscitis; one caused by S. epidermidis, the other by S. haemolyticus. Additionally, we reviewed the literature for previously reported cases of concomitant endocarditis and spondylodiscitis due to CoNS. Conclusion: In patients with back pain and a cardiac device in situ, CoNS should be considered as causative pathogens for possible endocarditis and/or spondylodiscitis, and should not be regarded as contamination.</p

    Induction of antibodies by Staphylococcus aureus nasal colonization in young children

    Get PDF
    AbstractIn order to develop novel antlstaphylococcal strategies, understanding the determinants of carriage and how humans respond to Staphylococcus aureus exposure is essential. Here, the primary S. aureus-specific humoral immune response and its association with nasal colonization was studied in young children. Sera from 57 colonized or non-colonized children, serially collected at birth and at 6, 14 and 24 months, were analysed for IgG, IgA and IgM binding to 19 staphylococcal proteins, using flow cytometry-based technology. The antibody responses showed extensive inter-individual variability. On average, the levels of antistaphylococcal IgA and IgM increased from birth until the age of 2 years (p <0.05), whereas the levels of IgG decreased (p <0.001). Placentally transferred maternal IgG did not protect against colonization. In colonized children, IgG and IgA levels for a number of proteins were higher than in non-colonized children. At both 14 and 24 months, the levels of IgG against chemotaxis inhibitory protein of S. aureus (at 24 months; median fluorescence intensity, 4928 vs. 24, p <0.05), extracellular fibrinogen-binding protein (987 vs. 604, p <0.05), and iron-responsive surface determinant H (62 vs. 5, p <0.05) were significantly higher in colonized children. The levels of IgA against CHIPS, IsdH and IsdA were higher (p <0.05). Therefore, CHIPS, Efb, IsdA and IsdH seem to play a role in nasal colonization of young children

    Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats

    Get PDF
    Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination

    KKF-Model Platform Coupling : summary report KKF01b

    Get PDF
    Nederland bereidt zich voor op een sneller stijgende zeespiegel en een veranderend klimaat. Hiervoor is het Deltaprogramma gestart. Dit deltaprogramma voorziet een serie beslissingen die grote gevolgen zullen hebben voor het beheer van het water in Nederland. Om deze beslissingen zorgvuldig te nemen is informatie nodig over hoe het klimaat en de stijgende zeespiegel dit waterbeheer zullen beïnvloeden. De modellen die de gevolgen van klimaatverandering berekenen zullen daarom met dezelfde klimaat forcering en gekoppeld aan elkaar moeten worden gebruikt. In dit onderzoek is gekeken naar het linken van hydrologische en hydrodynamische modellen – en daaraan gekoppelde modellen die de ontwikkelingen in natuur en landgebruik modelleren -- die het gebied van de Alpen tot en met de Noordzee inclusief Nederland beschrijven

    Neonatal stress exposure and DNA methylation of stress-related and neurodevelopmentally relevant genes:An exploratory study

    Get PDF
    Background: Stress exposure during Neonatal Intensive Care Unit (NICU) stay may have long-lasting effects on neurodevelopmental outcomes in extremely preterm infants. Altered DNA methylation of stress-related and neurodevelopmentally relevant genes may be an underlying mechanism.Aims: This exploratory study aimed to investigate the association between neonatal stress exposure and DNA methylation in these genes at two different time points: early during the NICU stay (7–14 days after birth) and later, at discharge from the NICU.Subjects: We included 45 extremely preterm infants in this prospective cohort study, gestational age 24–30 weeks.Outcome measures: We collected fecal samples at days 7–14 (n = 44) and discharge (n = 28) and determined DNA methylation status in predefined regions of NR3C1, SLC6A4, HSD11B2, OPRM1, SLC7A5, SLC1A2, IGF2, NNAT, BDNF and GABRA6 using pyrosequencing. Because of low DNA concentrations in some fecal samples, we could do so in 25–50 % of collected samples. We prospectively quantified daily neonatal stress exposure using the Neonatal Infant Stressor Scale (NISS) and explored associations between cumulative NISS scores and average DNA methylation status.Results: Rates of methylation of most genes were not statistically different between day 7–14 and discharge, except for OPRM1. We found moderately high and mostly negative correlation coefficients upon discharge with the cumulative NISS for the NR3C1, SLC6A4, SLC1A2, IGF2, BDNF and OPRM1 genes, albeit not statistically significant.Conclusions: Findings suggest that expression of stress-related and neurodevelopmentally relevant genes may be differently regulated following higher neonatal stress exposure. Larger studies should challenge the findings of this study and ideally test the effects on gene expression.</p

    Contact tracing for vancomycin-resistant Enterococcus faecium (VRE):evaluation of the Dutch policy of quintuple screening cultures

    Get PDF
    Detection of vancomycin-resistant Enterococcus faecium (VRE) is hampered by low sensitivity of rectal swab cultures. This study aimed to define the number of screening cultures needed to increase sensitivity to detect VRE transmission, and to determine time from presumed exposure to detectable colonization. In a tertiary care setting, we retrospectively analyzed data from 9 VRE outbreaks. As a proxy or estimation for time to detectable colonization, the time between first positive culture of the presumed index patient and that of their contacts was determined. Only 64% of secondary cases were positive in the first out of five cultures. By using the first three out of five rectal swabs, 89% (95%CI: 78–95%) of all secondary cases would have been identified. The median number of days between the positive culture of the index patient and the first positive culture of secondary cases was 9 days. Eleven percent of secondary cases would have been missed if only three rectal samples would have been obtained. Furthermore, our results show that one or more rectal swabs taken around day 9 after presumed exposure should at least be included in the screening approach. In our setting, obtaining a fourth and a fifth rectal swab showed a relevant additional value compared to only one to three swabs. Our findings are useful for determining the most effective VRE contact tracing approach to prevent transmission.</p

    Liquid racism and the Danish Prophet Muhammad cartoons

    Get PDF
    This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 The Author.This article examines reactions to the October 2005 publication of the Prophet Muhammad cartoons in the Danish newspaper Jyllands-Posten. It does so by using the concept of ‘liquid racism’. While the controversy arose because it is considered blasphemous by many Muslims to create images of the Prophet Muhammad, the article argues that the meaning of the cartoons is multidimensional, that their analysis is significantly more complex than most commentators acknowledge, and that this complexity can best be addressed via the concept of liquid racism. The article examines the liquidity of the cartoons in relation to four readings. These see the cartoons as: (1) a criticism of Islamic fundamentalism; (2) blasphemous images; (3) Islamophobic and racist; and (4) satire and a defence of freedom of speech. Finally, the relationship between postmodernity and the rise of fundamentalism is discussed because the cartoons, reactions to them, and Islamic fundamentalism, all contain an important postmodern dimension.ESR

    Gestational oxidative stress protects against adult obesity and insulin resistance

    Get PDF
    Pregnancy complications such as preeclampsia cause increased fetal oxidative stress and fetal growth restriction, and associate with a higher incidence of adult metabolic syndrome. However, the pathophysiological contribution of oxidative stress per se is experimentally difficult to discern and has not been investigated. This study determined, if increased intrauterine oxidative stress (IUOx) affects adiposity, glucose and cholesterol metabolism in adult Ldlr-/-xSod2+/+ offspring from crossing male Ldlr-/-xSod2+/+ mice with Ldlr-/-xSod2+/- dams (IUOx) or Ldlr-/-xSod2+/- males with Ldlr-/-xSod2+/+ dams (control). At 12 weeks of age mice received Western diet for an additional 12 weeks. Adult male IUOx offspring displayed lower body weight and reduced adiposity associated with improved glucose tolerance compared to controls. Reduced weight gain in IUOx was conceivably due to increased energy dissipation in white adipose tissue conveyed by higher expression of Ucp1 and an accompanying decrease in DNA methylation in the Ucp1 enhancer region. Female offspring did not show comparable phenotypes. These results demonstrate that fetal oxidative stress protects against the obesogenic effects of Western diet in adulthood by programming energy dissipation in white adipose tissue at the level of Ucp1