Multiple histone modifications in euchromatin promote heterochromatin formation by redundant mechanisms in Saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>Methylation of lysine 79 on histone H3 by Dot1 is required for maintenance of heterochromatin structure in yeast and humans. However, this histone modification occurs predominantly in euchromatin. Thus, Dot1 affects silencing by indirect mechanisms and does not act by the recruitment model commonly proposed for histone modifications. To better understand the role of H3K79 methylation gene silencing, we investigated the silencing function of Dot1 by genetic suppressor and enhancer analysis and examined the relationship between Dot1 and other global euchromatic histone modifiers.</p> <p>Result</p> <p>We determined that loss of H3K79 methylation results in a partial silencing defect that could be bypassed by conditions that promote targeting of Sir proteins to heterochromatin. Furthermore, the silencing defect in strains lacking Dot1 was dependent on methylation of H3K4 by Set1 and histone acetylation by Gcn5, Elp3, and Sas2 in euchromatin. Our study shows that multiple histone modifications associated with euchromatin positively modulate the function of heterochromatin by distinct mechanisms. Genetic interactions between Set1 and Set2 suggested that the H3K36 methyltransferase Set2, unlike most other euchromatic modifiers, negatively affects gene silencing.</p> <p>Conclusion</p> <p>Our genetic dissection of Dot1's role in silencing in budding yeast showed that heterochromatin formation is modulated by multiple euchromatic histone modifiers that act by non-overlapping mechanisms. We discuss how euchromatic histone modifiers can make negative as well as positive contributions to gene silencing by competing with heterochromatin proteins within heterochromatin, within euchromatin, and at the boundary between euchromatin and heterochromatin.</p

Incidence and management of Osgood-Schlatter disease in general practice:retrospective cohort study

BACKGROUND: Osgood–Schlatter disease (OSD) is a non-traumatic knee problem that is primarily observed in sports-active children and adolescents aged 8–15 years. AIM: To determine the incidence of OSD and to gain an insight into the management of children and adolescents with OSD in general practice. DESIGN AND SETTING: A retrospective cohort study was conducted using a healthcare database containing full electronic health records of over 200 000 patients in general practice in and around the Dutch city of Rotterdam. METHOD: Patients with a new diagnosis of OSD from 1 January 2012 to 31 December 2017 were extracted using a search algorithm based on International Classification of Primary Health Care coding and search terms in free text. Data on the management of OSD were manually interpreted. RESULTS: The mean incidence over the study period was 3.8 (95% confidence interval [CI] = 3.5 to 4.2) per 1000 person–years in those aged 8–18 years. Boys had a higher incidence rate of 4.9 (95% CI = 4.3 to 5.5) compared with girls (2.7, 95% CI = 2.3 to 3.2). Peak incidence was at 12 years of age for boys and 11 years for girls. Advice was the most commonly applied strategy (55.1%), followed by rest (21.0%), referral for imaging (19.5%), and physiotherapy (13.4%). CONCLUSION: To the authors’ knowledge, for the first time the incidence of OSD has been calculated using GP electronic medical files. There is a discrepancy, especially for imaging and referral to a medical specialist, between the current Dutch general practice guidelines and how GPs actually manage the condition in clinical practice

An approach to computing downward closures

The downward closure of a word language is the set of all (not necessarily contiguous) subwords of its members. It is well-known that the downward closure of any language is regular. While the downward closure appears to be a powerful abstraction, algorithms for computing a finite automaton for the downward closure of a given language have been established only for few language classes. This work presents a simple general method for computing downward closures. For language classes that are closed under rational transductions, it is shown that the computation of downward closures can be reduced to checking a certain unboundedness property. This result is used to prove that downward closures are computable for (i) every language class with effectively semilinear Parikh images that are closed under rational transductions, (ii) matrix languages, and (iii) indexed languages (equivalently, languages accepted by higher-order pushdown automata of order 2).Comment: Full version of contribution to ICALP 2015. Comments welcom

Dot1 binding induces chromatin rearrangements by histone methylation-dependent and -independent mechanisms

<p>Abstract</p> <p>Background</p> <p>Methylation of histone H3 lysine 79 (H3K79) by Dot1 is highly conserved among species and has been associated with both gene repression and activation. To eliminate indirect effects and examine the direct consequences of Dot1 binding and H3K79 methylation, we investigated the effects of targeting Dot1 to different positions in the yeast genome.</p> <p>Results</p> <p>Targeting Dot1 did not activate transcription at a euchromatic locus. However, chromatin-bound Dot1 derepressed heterochromatin-mediated gene silencing over a considerable distance. Unexpectedly, Dot1-mediated derepression was established by both a H3K79 methylation-dependent and a methylation-independent mechanism; the latter required the histone acetyltransferase Gcn5. By monitoring the localization of a fluorescently tagged telomere in living cells, we found that the targeting of Dot1, but not its methylation activity, led to the release of a telomere from the repressive environment at the nuclear periphery. This probably contributes to the activity-independent derepression effect of Dot1.</p> <p>Conclusions</p> <p>Targeting of Dot1 promoted gene expression by antagonizing gene repression through both histone methylation and chromatin relocalization. Our findings show that binding of Dot1 to chromatin can positively affect local gene expression by chromatin rearrangements over a considerable distance.</p

A Case Report of the Second de Novo Acute Myeloid Leukemia (AML) Following Allogeneic Stem Cell Transplantation in a Patient with the First AML

Secondary leukemia occurring after hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) is rare. Secondary AML usually follows autologous and not allogeneic transplants. When a new leukemia develops in a patient successfully treated with an allogeneic HSCT, the possibility of a de novo or secondary leukemia from either the donor or recipient should be considered. We present a case initially diagnosed as de novo AML without a cytogenetic abnormality. The patient was successfully treated with an HLA-matched sibling allogeneic HSCT. However, more than six years later, AML developed again and was associated with new complex cytogenetic abnormalities. After a second HSCT, the patient has been followed without serious complications. Considering the allogeneic setting, the newly developed cytogenetic abnormalities, a relatively long latent period, and the good clinical course after the second allogeneic HSCT, this case might represent a second de novo AML following successful treatment of the first AML

On the correlation between bibliometric indicators and peer review: reply to Opthof and Leydesdorff

Opthof and Leydesdorff (Scientometrics, 2011) reanalyze data reported by Van Raan (Scientometrics 67(3):491–502, 2006) and conclude that there is no significant correlation between on the one hand average citation scores measured using the CPP/FCSm indicator and on the other hand the quality judgment of peers. We point out that Opthof and Leydesdorff draw their conclusions based on a very limited amount of data. We also criticize the statistical methodology used by Opthof and Leydesdorff. Using a larger amount of data and a more appropriate statistical methodology, we do find a significant correlation between the CPP/FCSm indicator and peer judgment

Dutch translation and cross-cultural validation of the Adult Social Care Outcomes Toolkit (ASCOT)

Background: The Adult Social Care Outcomes Toolkit was developed to measure outcomes of social care in England. In this study, we translated the four level self-completion version (SCT-4) of the ASCOT for use in the Netherlands and performed a cross-cultural validation. Methods: The ASCOT SCT-4 was translated into Dutch following international guidelines, including two forward and back translations. The resulting version was pilot tested among frail older adults using think-aloud interviews. Furthermore, using a subsample of the Dutch ACT-study, we investigated test-retest reliability and construct validity and compared response distributions with data from a comparable English study. Results: The pilot tests showed that translated items were in general understood as intended, that most items were reliable, and that the response distributions of the Dutch translation and associations with other measures were comparable to the original English version. Based on the results of the pilot tests, some small modifications and a revision of the Dignity items were proposed for the final translation, which were approved by the ASCOT development team. The complete original English version and the final Dutch translation can be obtained after registration on the ASCOT website (http://www.pssru.ac.uk/ascot). Conclusions: This study provides preliminary evidence that the Dutch translation of the ASCOT is valid, reliable and comparable to the original English version. We recommend further research to confirm the validity of the modified Dutch ASCOT translation

Self-citations at the meso and individual levels: effects of different calculation methods

This paper focuses on the study of self-citations at the meso and micro (individual) levels, on the basis of an analysis of the production (1994–2004) of individual researchers working at the Spanish CSIC in the areas of Biology and Biomedicine and Material Sciences. Two different types of self-citations are described: author self-citations (citations received from the author him/herself) and co-author self-citations (citations received from the researchers’ co-authors but without his/her participation). Self-citations do not play a decisive role in the high citation scores of documents either at the individual or at the meso level, which are mainly due to external citations. At micro-level, the percentage of self-citations does not change by professional rank or age, but differences in the relative weight of author and co-author self-citations have been found. The percentage of co-author self-citations tends to decrease with age and professional rank while the percentage of author self-citations shows the opposite trend. Suppressing author self-citations from citation counts to prevent overblown self-citation practices may result in a higher reduction of citation numbers of old scientists and, particularly, of those in the highest categories. Author and co-author self-citations provide valuable information on the scientific communication process, but external citations are the most relevant for evaluative purposes. As a final recommendation, studies considering self-citations at the individual level should make clear whether author or total self-citations are used as these can affect researchers differently

A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

<p>Abstract</p> <p>Background</p> <p>Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study.</p> <p>Methods</p> <p>The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements.</p> <p>Discussion</p> <p>The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators.</p> <p>Trial registration</p> <p>NTR2922; <url>http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922</url></p