Biomedical subjects

Matthias Becker

Publications and source records attributed to Matthias Becker.

12 recordsLinked to original sources

PubMed2006

HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcription.

Although histone deacetylases (HDACs) are generally viewed as corepressors, we show that HDAC1 serves as a coactivator for the glucocorticoid receptor (GR). Furthermore, a subfraction of cellular HDAC1 is acetylated after association with the GR, and this acetylation event correlates with a decrease in promoter activity. HDAC1 in repressed chromatin is highly acetylated, while the deacetylase found on transcriptionally active chromatin manifests a low level of acetylation. Acetylation of purified HDAC1 inactivates its deacetylase activity, and mutation of the critical acetylation sites abrogates HDAC1 function in vivo. We propose that hormone activation of the receptor leads to progressive acetylation of HDAC1 in vivo, which in turn inhibits the deacetylase activity of the enzyme and prevents a deacetylation event that is required for promoter activation. These findings indicate that HDAC1 is required for the induction of some genes by the GR, and this activator function is dynamically modulated by acetylation.

Acetylation↗

PubMed2005

Differential in vivo binding dynamics of somatic and oocyte-specific linker histones in oocytes and during ES cell nuclear transfer.

The embryonic genome is formed by fusion of a maternal and a paternal genome. To accommodate the resulting diploid genome in the fertilized oocyte dramatic global genome reorganizations must occur. The higher order structure of chromatin in vivo is critically dependent on architectural chromatin proteins, with the family of linker histone proteins among the most critical structural determinants. Although somatic cells contain numerous linker histone variants, only one, H1FOO, is present in mouse oocytes. Upon fertilization H1FOO rapidly populates the introduced paternal genome and replaces sperm-specific histone-like proteins. The same dynamic replacement occurs upon introduction of a nucleus during somatic cell nuclear transfer. To understand the molecular basis of this dynamic histone replacement process, we compared the localization and binding dynamics of somatic H1 and oocyte-specific H1FOO and identified the molecular determinants of binding to either oocyte or somatic chromatin in living cells. We find that although both histones associate readily with chromatin in nuclei of somatic cells, only H1FOO is capable of correct chromatin association in the germinal vesicle stage oocyte nuclei. This specificity is generated by the N-terminal and globular domains of H1FOO. Measurement of in vivo binding properties of the H1 variants suggest that H1FOO binds chromatin more tightly than somatic linker histones. We provide evidence that both the binding properties of linker histones as well as additional, active processes contribute to the replacement of somatic histones with H1FOO during nuclear transfer. These results provide the first mechanistic insights into the crucial step of linker histone replacement as it occurs during fertilization and somatic cell nuclear transfer.

Animals↗

PubMed2005

Vitrectomy in the treatment of uveitis.

PURPOSE: To assess the evidence that pars plana vitrectomy (PPV) is useful in improving vision, reducing disease activity, or ameliorating cystoid macular edema (CME) in patients with uveitis. DESIGN: Review of the literature. METHODS: A Medline search was conducted for relevant articles published in English, German, or French. Articles were analyzed for content and evidence level. RESULTS: A total of 44 interventional case series published between 1981 and 2005 were identified that included 1575 patients (1762 eyes). Evidence level was grade CII-3 indicating possibly improved clinical outcomes with fair or poor evidence. The average age of patients was 36 years with a median duration of uveitis before surgery of 48 months and a median follow-up of 1.9 years. Intermediate uveitis was present in 841 eyes. Cystoid macular edema and cataract were common co-morbidities, and there were large numbers of additional surgical procedures. Visual outcomes in 39 articles were stated as improved in 708 eyes (68%), unchanged in 202 eyes (20%), and worsened in 124 eyes (12%). Reduction in systemic medication following PPV was reported in 25 studies. The median reported percentage of patients per study with CME was 36% preoperatively and 18% postoperatively. CONCLUSIONS: Based on the evidence in the literature, PPV is possibly relevant to the outcomes of improving vision and reducing inflammation and CME. Randomized, controlled, collaborative trials or hypothesis-based case series with precise outcome measures that incorporate control groups would improve the quality of evidence supporting PPV as an adjunct to the medical treatment of uveitis.

Adolescent↗

PubMed2005

Qigong for schoolchildren: a pilot study.

OBJECTIVE: To evaluate the effects of qigong lessons on schoolchildren in terms of their achievements at school, social behavior, and general health. DESIGN: A controlled intervention pilot study was conducted with children in two second-grade classes at an elementary school and in two eighth-grade classes at a high school. SETTING/LOCATION AND INTERVENTION: One class from each school received qigong lessons for 20 minutes at least twice weekly over a period of 6 months, while the control class from the same school received no intervention. Two additional classes at two elementary schools participated in the qualitative analysis only. MEASURES: Teachers, parents, and students answered standardized questionnaires at the beginning of the study and after 6 months, covering complaints, concentration, creativity, grades, quality of life (QOL) (assessed by the KINDL questionnaire), and social behavior. In addition to this quantitative study, we conducted in-depth, semi-structured interviews with all participating teachers at the end of the project to evaluate individual effects. RESULTS: Of a total of 90 participants in the study (52% boys and 48% girls), 40 students attended elementary school (20 per class, mean age 7.4 +/- 0.5 years) and 50 high school (25 per class, mean age 13 +/- 0.8 years). Factor analysis yielded three scales for the teacher questionnaire (learning process, social behavior, appropriate behavior) and four scales for the parent questionnaire (creativity, concentration, well-being, restlessness). The qigong group showed significantly better results in the teacher questionnaire (especially for appropriate behavior) and in grades in comparison to the control group, but no effect was found in the parent questionnaire, medical complaints, sick days, or in the children's assessment of QOL. Qualitative analyses indicated a relevant decrease of individual complaints for some children in the qigong group. CONCLUSIONS: The feasibility of integrating qigong in school lessons was shown. Six months after starting qigong lessons, schoolchildren improved in social behavior and showed stable grades, while inappropriate behavior decreased, compared to the control. Combining quantitative and qualitative research methods appeared to be useful to detect the effects of qigong in individuals. Due to the limitations of our pilot study, further studies with larger sample sizes and long-term follow-up are needed.

Adolescent↗

PubMed2005

Central angiotensin II controls alcohol consumption via its AT1 receptor.

Pharmacological and genetic manipulations of the renin-angiotensin system (RAS) have been found to alter the voluntary consumption of alcohol. Here we characterize the role of central angiotensin II (Ang II) in alcohol intake first by using transgenic rats that express an antisense RNA against angiotensinogen and consequently have reduced Ang II levels exclusively in the central nervous system [TGR(ASrAOGEN)680]. These rats consumed markedly less alcohol in comparison to their wild-type controls. Second, Spirapril, an inhibitor of the angiotensin-converting enzyme (ACE), which passes the blood-brain barrier, did not influence the alcohol consumption in the TGR(ASrAOGEN)680, but it significantly reduced alcohol intake in wild-type rats. Studies in knockout mice indicated that the central effect of Ang II on alcohol consumption is mediated by the angiotensin receptor AT1 whereas the AT2 receptor and the bradykinin B2 receptor are not involved. Furthermore, the dopamine concentration in the ventral tegmental area (VTA) is markedly reduced in rats with low central Ang II, strengthening our hypothesis of a role of dopaminergic transmission in Ang II-controlled alcohol preference. Our results indicate that a distinct drug-mediated control of the central RAS could be a promising therapy for alcohol disease.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Transpalpebral measurement of intraocular pressure using the TGDc-01 tonometer versus standard Goldmann applanation tonometry.

BACKGROUND: A recently developed digital tonometer for transpalpebral intraocular pressure (IOP) measurement, distributed by Corneal, Inc., allows the noninvasive measurement of IOP for screening purposes. METHOD: We measured the IOP of 218 eyes in 109 patients of the Interdisciplinary Uveitis Center of the University of Heidelberg with intact corneal epithelium. IOPs were measured first with the TGDc-01 tonometer, and then by means of Goldmann tonometry. IOPs were recorded by two independent examiners. The mean of three measurements obtained with the TGDc-01 was taken, whereas only one measurement was performed with the Goldmann tonometer. RESULTS: The mean difference between the TGDc-01 and Goldmann measurements was 3.7 mmHg. The standard deviation of the differences was +/-4.06 mmHg. Thus measurements acquired with the TGDc-01 may range 4.4 mmHg above or 11.8 mmHg below the values given by Goldmann tonometry. CONCLUSION: The IOP values obtained with the TGDc-01 were in poor agreement with Goldmann tonometry. We found a higher variation as well as a bias towards lower IOP values with the TGDc-01. It is a question of clinical judgement as to how far these deviating measurements can be accepted for screening purposes. Because the IOPs obtained with the TGDc-01 are generally lower and less accurate than those obtained with the Goldmann tonometer we believe that the TGDc-01 is not a reliable tool for IOP measurement in clinical routine.

Eyelids↗

PubMed2004

H1FOO is coupled to the initiation of oocytic growth.

We previously reported the discovery of a novel mammalian H1 linker histone termed H1FOO (formerly H1OO), a replacement H1, the expression of which is restricted to the growing/ maturing oocyte and to the zygote. The significance of this pre-embryonic H1 draws on its substantial orthologous conservation, singular structural attributes, selectivity for the germ cell lineage, prolonged nucleosomal residence, and apparent predominance among germ cell H1s. Herein, we report that the intronic, single-copy, five-exon (> or =5301 base pair) H1foo gene maps to chromosome 6 and that the corresponding primary H1foo transcript gives rise to two distinct, alternatively spliced mRNA species (H1foo(alpha) and H1foo(beta)). The expression of the oocytic H1FOO transcript and protein proved temporally coupled to the recruitment of resting primordial follicles into a developing primary follicular cohort and thus to the critical transition marking the onset of oocytic growth. The corresponding potential protein isoforms (H1FOO(alpha) and H1FOO(beta)), both nuclear localization sequence-endowed but export consensus sequence-free and possessing a significant net positive charge, localized primarily to perinucleolar heterochromatin in the oocytic germinal vesicle. Further investigation will be required to define the functional role of the H1FOO protein in the ordering of the chromatin of early mammalian development as well as its potential role in defining the primordial-to-primary follicle transition.

Alternative Splicing↗

PubMed2004

Subnuclear trafficking and gene targeting by steroid receptors.

Through the use of novel imaging techniques, we have observed direct steroid receptor binding to a tandem array of a hormone-responsive promoter in living cells. We found that the glucocorticoid receptor (GR) exchanges rapidly with regulatory elements in the continued presence of ligand. We have also reconstituted a GR-dependent nucleoprotein transition with chromatin assembled on promoter DNA, and we discovered that GR is actively displaced from the chromatin template during the chromatin remodeling process. Using high-intensity UV laser crosslinking, we have observed highly periodic interactions of GR with promoter chromatin. These periodic binding events are dependent on GR-directed hSWI/SNF remodeling of the template and require the presence of ATP. Both the in vitro and in vivo results are consistent with a dynamic model ("hit-and-run") in which GR first binds to chromatin after ligand activation, recruits a remodeling activity, and is simultaneously lost from the template. We also find that receptor mobility in the nucleoplasm is strongly enhanced by molecular chaperones. These observations indicate that multiple mechanisms are involved in transient receptor interactions with nucleoplasmic targets.

Animals↗

PubMed2004

Biochemical analysis of neutral endopeptidase activity reveals independent catabolism of atrial and brain natriuretic peptide.

Recent reports presented contradictory results regarding the catabolism of mature atrial (ANP) and brain (BNP) natriuretic peptides in circulation. Especially the role of neutral endopeptidase (NEP) in BNP degradation was conversely discussed. Our present in vitro-studies characterize the NEP-dependent metabolism of ANP and BNP in different tissues via HPLC-analysis using NEP-deficient mice and specific NEP inhibitors. Our results show a strong tissue-dependent degradation pattern of both peptides, which are not only due to the different NEP activities in these tissues. Whereas NEP rapidly degraded ANP, it had no influence in BNP-metabolism. Additional experiments with purified NEP confirmed this result. Moreover, we describe a degradation of ANP and BNP in NEP-deficient- and NEP-inhibited membranes. Consequently, we postulate the existence of at least one further natriuretic peptide (NP) degrading enzyme, which has not been characterized yet. Thus, the commonly accepted model of the natriuretic peptide system with NEP as the central degrading peptidase has to be partly revised. Moreover, the NEP-independent BNP degradation provides an effective means for achieving a beneficial BNP increase in cardiovascular pathology by inhibiting the assumed novel NP-degrading peptidase(s).

Animals↗

PubMed2003

Urochordates and the origin of natural killer cells: identification of a CD94/NKR-P1-related receptor in blood cells of Botryllus.

Transplantation immunity based on the recognition of MHC molecules is well described in vertebrates. Vertebrates, however, do not undergo transplantation reaction naturally. The phylogenetically closest group in which transplantation reactions can occur is the Urochordata. Therefore, these animals occupy a key position for understanding the evolution of the vertebrate immune system. When screening for genes differentially expressed during allorecognition in Botryllus schlosseri, we isolated a gene coding for a type II transmembrane protein with a C-type lectin-binding domain and close similarity to vertebrates CD94 and NKR-P1. Here we show that the gene, BsCD94-1, is differentially regulated during allorecognition and that a subpopulation of blood cells carries the corresponding receptor on its cell surface. Southern blot analysis with DNA from individual colonies and intronless BsCD94-1 probe reveal variation between individuals at the genomic level. CD94 in vertebrates is one of the markers for natural killer cells and binds to MHC class I molecules. Natural killer cells play a major role in recognition and elimination of allogeneic cells. Their evolutionary origin, however, remained unknown. The results presented here indicate that the elaboration of the vertebrate immune system may have its roots in an ancestral population of cells in the urochordate blood.

Amino Acid Sequence↗

PubMed2002

Dynamic behavior of transcription factors on a natural promoter in living cells.

Through the use of photobleaching techniques, we examined the dynamic interaction of three members of the transcription apparatus with a target promoter in living cells. The glucocorticoid receptor (GR) interacting protein 1 (GRIP-1) exhibits a half maximal time for fluorescent recovery (tau(R)) of 5 s, reflecting the same rapid exchange as observed for GR. In contrast, the large subunit (RPB1) of RNA polymerase II (pol II) required 13 min for complete fluorescence recovery, consistent with its function as a processive enzyme. We also observe a complex induction profile for the kinetics of GR-stimulated transcription. Our results indicate that GR and GRIP-1 as components of the activating complex are in a dynamic equilibrium with the promoter, and must return to the template many times during the course of transcriptional activation.

Animals↗

PubMed2002

Protein dynamics in the nuclear compartment.

The classic view of a transcriptional initiation complex is that of an assembly of factors with many protein-protein contacts, leading to a multi-component complex whose existence is a result of the stabilizing influence of the many intermolecular interactions. Recent findings from protein mobility experiments in living cells indicate that many kinds of nuclear factors move rapidly and exchange quickly with multiple targets. Two countervailing views of factor/regulatory site interactions emerge from the current literature.

Animals↗