Modal particles in Dutch as a second language, Evidence from a perception experiment

Interdisciplinary domains LUC

The perception of modal particles in Dutch as a second language

Fonetische correlaten en communicatieve functies van linguïstische structuu

Protocol of the Double-Click Seq Method to Evaluate the Deposition Bias of Chromatin Proteins

Symmetrical deposition of parental and newly synthesized chromatin proteins over both sister chromatids is important for the maintenance of epigenetic integrity. However, the mechanisms to maintain equal distribution of parental and newly synthesized chromatid proteins over sister chromatids remains largely unknown. Here, we describe the protocol for the recently developed double-click seq method that enables mapping of asymmetry in the deposition of parental and newly synthesized chromatin proteins on both sister chromatids in DNA replication. The method involved metabolic labeling of new chromatin proteins with l-Azidohomoalanine (AHA) and newly synthesized DNA with Ethynyl-2′-deoxyuridine (EdU) followed by two subsequent click reactions for biotinylation and subsequently by corresponding separation steps. This enables isolation of parental DNA that was bound to nucleosomes containing new chromatin proteins. Sequencing of these DNA samples and mapping around origins of replication in the cellular DNA enables estimation of the asymmetry in deposition of chromatin proteins over the leading and lagging strand in DNA replication. Altogether, this method contributes to the toolbox to understand histone deposition in DNA replication.</p

Identification of a Bromodomain-like region in 15-Lipoxygenase-1 explains its Nuclear Localization

Lipoxygenase (LOX) activity provides oxidative lipid metabolites, which are involved in inflammatory disorders and tumorigenesis. Activity‐based probes to detect the activity of LOX enzymes in their cellular context provide opportunities to explore LOX biology and LOX inhibition. Here, we developed Labelox B as a potent covalent LOX inhibitor for one‐step activity‐based labeling of proteins with LOX activity. Labelox B was used to establish an ELISA‐based assay for affinity capture and antibody‐based detection of specific LOX isoenzymes. Moreover, Labelox B enabled efficient activity‐based labeling of endogenous LOXs in living cells. LOX proved to localize in the nucleus, which was rationalized by identification of a functional bromodomain‐like consensus motif in 15‐LOX‐1. This indicates that 15‐LOX‐1 is not only involved in oxidative lipid metabolism, but also in chromatin binding, which suggests a potential role in chromatin modifications

Longitudinal associations of multiple physical symptoms with recurrence of depressive and anxiety disorders

Objective To examine longitudinal associations of multiple physical symptoms with recurrence of depressive and anxiety disorders. Methods Follow-up data of 584 participants with remitted depressive or anxiety disorders were used from the Netherlands Study of Depressive and Anxiety disorders. Multiple physical symptoms were measured at baseline (T1) and two-year follow-up (T2) by the Four-Dimensional Symptom Questionnaire (4DSQ) somatization subscale. Recurrence of depressive and anxiety disorders was assessed at two-year (T2) and four-year (T4) follow-up with the Composite International Diagnostic Interview. Logistic Generalized Estimating Equations were used to examine associations of multiple physical symptoms with recurrence of depressive and anxiety disorders. Depressive (IDS-SR) and anxiety symptoms (BAI), and other relevant covariates were taken into account. Results Multiple physical symptoms were significantly associated with recurrence of depression (OR = 1.04, 95%CI = 1.00–1.08), anxiety (OR = 1.07, 95%CI = 1.03–1.12), and depressive or anxiety disorders (OR = 1.06, 95%CI = 1.02–1.10), on average over time. Odds ratios did not change substantially when the IDS-SR mood-cognition and BAI subjective scale were included as covariates. Conclusion The presence of multiple physical symptoms was positively related to recurrence of depressive and anxiety disorders, independent of depressive and anxiety symptoms. Knowledge of risk factors for recurrence of depressive and anxiety disorders, such as the presence of multiple physical symptoms, could provide possibilities for better targeting interventions to prevent recurrence

Epidemiology of unintentional injuries in childhood: a population-based survey in general practice

This study aimed to assess the incidence of unintentional injuries presented in general practice, and to identify children at risk from experiencing an unintentional injury. We used the data of all 0-17-year-old children from a representative survey in 96 Dutch general practices in 2001. We computed incidence rates and multilevel multivariate regression analysis in different age strata and identified patient and family characteristics associated with an elevated injury risk. Nine thousand four hundred and eighty-four new injury episodes were identified from 105 353 new health problems presented in general practice, giving an overall incidence rate of 115 per 1000 person years (95% confidence interval [CI] = 113 to 118). Sex and residence in rural areas are strong predictors of injury in all age strata. Also, in children aged 0-4 years, a higher number of siblings is associated with elevated injury risk (> or =3 siblings odds ratio [OR] = 1.57, 95% CI = 1.19 to 2.08) and in the 12-17-year-olds, ethnic background and socioeconomic class are associated with experiencing an injury (non-western children OR = 0.67, 95% CI = 0.54 to 0.81; low socioeconomic class OR = 1.39, 95% CI = 1.22 to 1.58). Unintentional injury is a significant health problem in children in general practice, accounting for 9% of all new health problems in children. In all age groups, boys in rural areas are especially at risk to experience an injury

Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC)

Histone deacetylases (HDACs) play important roles in inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD). Unravelling of and interfering with the functions of specific isoenzymes contributing to inflammation provides opportunities for drug development. Here we synthesize proteolysis targeting chimeras (PROTACs) for degradation of class I HDACs in which o-aminoanilide-based class I HDAC inhibitors are tethered to the cereblon ligand pomalidomide. One of these PROTACs, denoted HD-TAC7, showed promising degradation effects for HDAC3 with a DC50 value of 0.32 μM. In contrast to biochemical evidence using siRNA, HD-TAC7 showed a minimal effect on gene expression in LPS/IFNγ-stimulated RAW 264.7 macrophages. The lack of effect can be attributed to downregulation of the NF-κB subunit p65, which is a known side effect of pomalidomide treatment. Altogether, we describe a novel PROTAC that enables selective downregulation of HDAC3 levels, however we note that concomitant downregulation of the NF-κB subunit p65 can confound the biological outcome

Development and psychometric properties of a pain-related problem list for adolescents (PPL)

Instruments for measuring pain-related problems in adolescents with chronic pain are sparse, especially those based on the personal experiences of these adolescents. This study aimed to develop and test such an instrument, the pain-related problem list for adolescents (PPL). A sample of 129 adolescents with chronic pain without documented physiological etiology completed the 57-item problem list, which was based on interviews with a similar group of adolescents with chronic pain. Principal components analysis yielded four domains: problems related to (1) concentration; (2) mobility; (3) adaptability; and (4) mood. The questionnaire was shortened to 18 items and has good reliability (total α = 0.82; concentration α = 0.86; mobility α = 0.77; adaptability α = 0.71; and mood α = 0.78); the validity also proved to be adequate, especially in the general population sample. The PPL provides a tool to assess the impact of chronic pain in adolescents. Future research should focus on further validation of the PPL in a large clinical population and establishing its test-retest reliability

A cognitive-behavioural program for adolescents with chronic pain - A pilot study

The purpose of this pilot study is to evaluate the feasibility of a cognitive-behavioural training program for adolescents with chronic pain irrespective of pain localisation. A secondary aim was to give an impression of the effect of the program on pain and quality of life. Eight adolescents (14-18 years) with chronic non-organic pain recruited from the general population (and their parents) participated in this pilot study. The intervention included five group meetings alternated with four telephone contacts (during the self-management weeks) over a period of 9 weeks. The training aimed to change pain behaviour through pain education, relaxation strategies, problem-solving techniques, assertiveness training, cognitive restructuring and by stimulating the adolescent's physical activity level. The training further addresses the social context of pain by inviting parents to attend two meetings for the parents only, and by asking the adolescents to bring a peer to one of the meetings. Adolescents and their parents were positive about the program. Adolescents felt they were more in control of their pain and parents valued the support they experienced in helping their children to master the pain. The training was considered to be feasible in daily life. Further, the preliminary data showed an effect on pain and quality of life in the expected direction. The results underline the need for a definitive study with a larger sample size and a random controlled design