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Biomedical subjects

U Friedrich

Publications and source records attributed to U Friedrich.

At least 19 recordsLinked to original sources
PubMed2006

Gravitational biology within the German Space Program: goals, achievements, and perspectives.

Gravity plays an important role for the evolution, orientation and development of organisms. Most of us, however, tend to overlook its importance because--due to its constant presence from the beginning of evolution some 4 billion years ago--this environmental parameter is almost hardwired into our interpretation of reality. This negligence of gravity is the more surprising as we all have our strong fights with this factor, especially during the very early and again during the late phases of our lives. On the other hand, scientists have been fascinated to observe the effects of gravity especially on plants and microorganisms for more than a hundred years, since Darwin and Sachs demonstrated the role of the root cap for downward growing plants. Different experimental approaches are nowadays available in order to change the influence of gravity and to study the corresponding influences on the physiology of biological systems. With the advent of spaceflight, a long-term nearly nullification of gravity is possible. Utilisation of this so-called "microgravity" condition for research in life sciences thus became an important asset in the space programs of various space agencies around the world. The German Space Life Sciences Program is managed--like all other space programs and activities in Germany--by the German Aerospace Center (DLR) in its role as space agency for Germany. Within the current space program, approved by the German government in May 2001, the overall goal for its life sciences part was defined as to gain scientific knowledge and to disclose new application potential by research under space conditions, especially by utilising the microgravity environment of the International Space Station. Three main scientific fields have been identified in collaboration with the scientific community: integrative human physiology, biotechnological applications of the microgravity environment, and fundamental biology of gravity and radiation responses (i.e., gravitational and radiation biology). In the present contribution, specific goals as well as achievements and perspectives of research in gravitational biology are given. In addition, some information is provided on spaceflight opportunities available.

Animals↗
PubMed2005

Trisomy 3q25.1-qter and monosomy 8p23.1-pter in a patient: cytogenetic and molecular analysis with delineation of the phenotype.

We describe a 4-year-old boy with partial 3q trisomy and distal 8p monosomy. The patient presented with mental retardation, dysmorphic face, congenital heart defect, brain and genital anomalies, and behavioral problems. The conventional cytogenetic analysis showed a 46,XY,add(8p) karyotype. Reverse painting and microsatellite analysis demonstrated a partial monosomy of 8p23.1 --> pter and a partial trisomy of 3q25.1 --> qter. The data suggest that the chromosomal rearrangement originated from a de novo translocation in a paternal germinal cell. The phenotype observed in our patient resulted from the combination of those defects described in the isolated dup(3q) and distal del(8p) syndromes.

Child, Preschool↗
PubMed2005

Breakpoints around the HOXD cluster result in various limb malformations.

BACKGROUND: Characterisation of disease associated balanced chromosome rearrangements is a promising starting point in the search for candidate genes and regulatory elements. METHODS: We have identified and investigated three patients with limb abnormalities and breakpoints involving chromosome 2q31. Patient 1 with severe brachydactyly and syndactyly, mental retardation, hypoplasia of the cerebellum, scoliosis, and ectopic anus, carries a balanced t(2;10)(q31.1;q26.3) translocation. Patient 2, with translocation t(2;10)(q31.1;q23.33), has aplasia of the ulna, shortening of the radius, finger anomalies, and scoliosis. Patient 3 carries a pericentric inversion of chromosome 2, inv(2)(p15q31). Her phenotype is characterised by bilateral aplasia of the fibula and the radius, bilateral hypoplasia of the ulna, unossified carpal bones, and hypoplasia and dislocation of both tibiae. RESULTS: By fluorescence in situ hybridisation, we have mapped the breakpoints to intervals of approximately 170 kb or less. None of the three 2q31 breakpoints, which all mapped close to the HOXD cluster, disrupted any known genes. CONCLUSIONS: Hoxd gene expression in the mouse is regulated by cis-acting DNA elements acting over distances of several hundred kilobases. Moreover, Hoxd genes play an established role in bone development. It is therefore very likely that the three rearrangements disturb normal HOXD gene regulation by position effects.

Adolescent↗
PubMed2005

New prenylated benzoic acid derivatives of Piper hispidum.

Three new 4-hydroxy-benzoic acid derivatives, 4-methoxy-3,5-bis-(3-hydroxy-3-methyl-1-butenyl)benzoate, 3-hydroxy-2-(1-hydroxy-1-methylethyl)-2,3-dihydrobenzofuran-5-carboxylic acid, and 3-hydroxy-2-(1-hydroxy-1-methylethyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester together with eight known compounds, have been isolated from the stems of Piper hispidum. Their structures were elucidated by a detailed spectroscopic analysis. In addition, the cytotoxicity of seven isolated compounds has been evaluated, revealing a moderate activity for three derivatives of dillapiole.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Cytotoxicity of plants used in traditional medicine in Yemen.

Twenty-five extracts obtained from 14 plant species used in the traditional medicine in Yemen have been screened for cytotoxic activity against human ECV-304 cells. Extracts of Dracaena cinnabari, Eucalyptus camaldulensis, Euclea divinorum, Euphorbia cactus, Pulicaria crispa, and Withania somnifera displayed a remarkable activity.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Evidence of decreased risk of cancer in individuals with fragile X.

The occurrence of cancer was studied in a cohort of 223 persons with fragile X syndrome, based on information from the Danish Cytogenetic Registry and the Danish Cancer Registry. Four cases of cancer were found, (carcinoma of pancreas, urinary bladder, uterus, and rectum). None of these cancer types have been reported in patients with fragile X syndrome previously. Compared with cancer rates in the general population, the standardized incidence ratio (SIR) was decreased to 0.28 (95% confidence interval: 0.1-0.8). The possibility that the expanded trinucleotide repeats in fragile X syndrome protect against cancer is discussed.

Adolescent↗
PubMed2001

Structural and energetic characteristics of the heparin-binding site in antithrombotic protein C.

Human activated protein C (APC) is a key component of a natural anticoagulant system that regulates blood coagulation. In vivo, the catalytic activity of APC is regulated by two serpins, alpha1-antitrypsin and the protein C inhibitor (PCI), the inhibition by the latter being stimulated by heparin. We have identified a heparin-binding site in the serine protease domain of APC and characterized the energetic basis of the interaction with heparin. According to the counter-ion condensation theory, the binding of heparin to APC is 66% ionic in nature and comprises four to six net ionic interactions. To localize the heparin-binding site, five recombinant APC variants containing amino acid exchanges in loops 37, 60, and 70 (chymotrypsinogen numbering) were created. As demonstrated by surface plasmon resonance, reduction of the electropositive character of loops 37 and 60 resulted in complete loss of heparin binding. The functional consequence was loss in heparin-induced stimulation of APC inhibition by PCI, whereas the PCI-induced APC inhibition in the absence of heparin was enhanced. Presumably, the former observations were due to the inability of heparin to bridge some APC mutants to PCI, whereas the increased inhibition of certain APC variants by PCI in the absence of heparin was due to reduced repulsion between the enzymes and the serpin. The heparin-binding site of APC was also shown to interact with heparan sulfate, albeit with lower affinity. In conclusion, we have characterized and spatially localized the functionally important heparin/heparan sulfate-binding site of APC.

Amino Acid Sequence↗
PubMed2001

Secondary substrate-binding exosite in the serine protease domain of activated protein C important for cleavage at Arg-506 but not at Arg-306 in factor Va.

Proteolytic inactivation of activated factor V (FVa) by activated protein C (APC) is a key reaction in the regulation of hemostasis. We now demonstrate the importance of a positive cluster in loop 37 of the serine protease (SP) domain of APC for the degradation of FVa. Lysine residues in APC at positions 37, 38, and 39 form a secondary binding site for FVa, which is important for cleavage of FVa at Arg-506 while having no effect on Arg-306 cleavage. In contrast, topological neighbors Lys-62, Lys-63, and Arg-74 in APC appear of minor importance in FVa degradation. This demonstrates that secondary binding exosites of APC specifically guide the proteolytic action of APC, resulting in a more favorable degradation of the 506-507 peptide bond as compared with the 306-307 bond.

Arginine↗
PubMed2001

Multiparametric microsensor chips for screening applications.

The identification of drug targets for pharmaceutical screening can be greatly accelerated by gene databases and expression studies. The identification of leading compounds from growing libraries is realized by high throughput screening platforms. Subsequently, for optimization and validation of identified leading compounds studies of their functionality have to be carried out, and just these functionality tests are a limiting factor. A rigorous preselection of identified compounds by in vitro cellular screening is necessary prior to using the drug candidates for the further time consuming and expensive stage, e.g. in animal models. Our efforts are focused to the parallel development, adaptation and integration of different microelectronic sensors into miniaturized biochips for a multiparametric, functional on-line analysis of living cells in physiologically environments. Parallel and on-line acquisition of data related to different cellular targets is required for advanced stages of drug screening and for economizing animal tests.

Biocompatible Materials↗
PubMed2001

Application of rRNA-targeted oligonucleotide probes in biotechnology.

Ribosomal RNA-targeted oligonucleotide probes have become valuable tools for the detection of microorganisms involved in important biotechnological processes. Microorganisms which are of major importance for processes such as wastewater treatment, microbial leaching or methane production can be detected and quantified in situ within a complex microbial community. For certain processes, such as nitrification or biological phosphate removal, new microorganisms have become the focus of interest and have led to an improved understanding of these bioremediation techniques. Hybridization techniques have become fast and reliable alternatives to conventional cultivation techniques in the food industry as a control method for starter cultures for fermentation processes or product control. Recent analytical tools such as flow cytometry and digital image processing have improved the efficiency of these techniques. This review is intended to present a summary of methodological aspects of rRNA-based hybridization techniques and their application in biotechnology.

Bioreactors↗
PubMed2001

Down-regulation of Akt/PKB in senescent cardiac fibroblasts impairs PDGF-induced cell proliferation.

OBJECTIVE: Cardiovascular diseases are the leading cause of death in the Western World, especially in the elder population. One pathophysiological component of cardiovascular disease is myocardial fibrosis, primarily derived from cardiac fibroblasts. Here we investigated the regulation of proliferation of fibroblasts from hearts of adult rats by platelet derived growth factor AA (PDGF-AA). METHODS: Cardiac fibroblasts were isolated from adult Wistar rats. PDGF-induced cell proliferation was analysed by FACS. PDGF-receptor numbers were analysed by receptor binding assays. Using differential display, differentially expressed kinases were identified during ageing in vitro and confirmed by Northern and Western blotting. Transient overexpression of IRES-GFP constructs was used to analyse the role of the akt kinase on proliferation by FACS. RESULTS: During in vitro senescence/aging of primary fibroblasts, the growth response to PDGF-AA was greatly reduced without alterations in its receptor number or affinity and without changes in downstream signalling via the MAP-kinase pathway. By using a differential display strategy selective for protein kinases, we identified reduced expression of Akt-1 kinase (PKB-alpha) in senescent rat cardiac fibroblasts. These findings were supported by data showing reduced expression of Akt-1 in heart samples from old humans. Overexpression of activated Akt-1 almost completely reconstituted PDGF-AA dependent cell proliferation in aged fibroblasts. CONCLUSION: These results support an important role for Akt in senescence and regulation of cardiac fibroblast cell proliferation.

Animals↗
PubMed2001

Screening the molecular surface of human anticoagulant protein C: a search for interaction sites.

Protein C (PC), a 62 kDa multi-modular zymogen, is activated to an anticoagulant serine protease (activated PC or APC) by thrombin bound to thrombomodulin on the surface of endothelial cells. PC/APC interacts with many proteins and the characterisation of these interactions is not trivial. However, molecular modelling methods help to study these complex biological processes and provide basis for rational experimental design and interpretation of the results. PC/APC consists of a Gla domain followed by two EGF modules and a serine protease domain. In this report, we present two structural models for full-length APC and two equivalent models for full-length PC, based on the X-ray structures of Gla-domainless APC and of known serine protease zymogens. The overall elongated shape of the models is further cross-validated using size exclusion chromatography which allows evaluation of the Stokes radius (rs for PC = 33.15 A; rs for APC = 34.19 A), frictional ratio and axial ratio. We then propose potential binding sites at the surface of PC/APC using surface hydrophobicity as a determinant of the preferred sites of intermolecular recognition. Most of the predicted binding sites are consistent with previously reported experimental data, while some clusters highlight new regions that should be involved in protein-protein interactions.

Amino Acid Sequence↗
PubMed2001

Herpesvirus saimiri Tip gene causes T-cell lymphomas in transgenic mice.

New World primates develop T-cell lymphomas on infection with Herpesvirus saimiri. To investigate the oncogenic potential of the Tip gene of Herpesvirus saimiri strain C488, we tried to establish transgenic mice that should express Tip under control of a constitutive promoter. Although transgene-positive embryos were found, lines could not be established. However, using a system in which the transgene has to be activated by a Cre recombinase-mediated deletion, we were able to obtain several Tip transgenic lines. At high expression levels, the mice developed T-cell lymphomas. Thus, Tip can induce lymphomas and is therefore very likely responsible for the oncogenicity of Herpesvirus saimiri.

Animals↗
PubMed2001

Telomeres in neonates: new insights in fetal hematopoiesis.

Progressive telomere shortening occurs in somatic cells, and with increasing donor age a significant decline in telomere length has been shown in various postnatal tissues. In contrast, little is known about changes in telomere length during human fetal development. Therefore, we measured telomere length in the leukocyte fraction of umbilical cord blood samples from 15 preterm (<37 wk of gestation) and 11 full-term (>37 wk of gestation) neonates using the telomere restriction fragment assay. Whereas no differences in mean (+/- SD) telomere restriction fragment between the groups of preterm neonates (8512 +/- 523 bp) and full-term newborns (8323 +/- 503 bp) could be found, significantly longer telomeres (p = 0.002) were found in very low birth weight preterm neonates when compared with low birth weight preterm neonates. In addition, a rapid and significant decline in mean telomere restriction fragment was observed between 27 and 32 wk of gestation (p = 0.02, r = 0.79) followed by a period of no significant loss of telomere repeats between 33 and 42 wk of gestation. These results are consistent with the known almost maximal proliferation rate of hematopoietic progenitor cells before 32 wk of gestation. The initial decrease in telomere restriction fragment could be caused by ontogeny-related functional alterations of hematopoietic cells or differences in stem cell turnover or the rate of telomere loss per cell division.

Fetus↗
PubMed2000

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Adolescent↗