Biomedical subjects

M Noll

Publications and source records attributed to M Noll.

At least 19 recordsLinked to original sources

PubMed2003

Recurrent arachnoid cyst of Meckel's cave mimicking a brain stem ischaemia. Report of a rare case.

UNLABELLED: A 44-years old man developed TIA-like symptoms with dysaesthesia around the mouth, vertigo and diplopia. MRI revealed a cystic space-occupying lesion on the right Meckel's cave, which spread out into cerebellopontine angle in a further examination. Therefore surgical exploration was performed using a suboccipital approach. An arachnoidal cyst was found and removed including its wall. About three months later the patient suffered again from dysaesthesias of the right side of the face and a new MRI revealed a recurrence of the lesion, with extension into the cerebellopontine angle, too. Surgical revision was done using the same approach and the recurrent cyst was removed. Postoperatively, there were a transient hypaesthesia in the distribution area of the right trigeminal nerve and a light pulmonary embolism occurred as a complication. No symptoms have returned during an observation period of 15 months. CONCLUSION: An arachnoidal cyst must be considered as a rare cause, when a lesion is found at the Meckel's cave with intermittent clinical symptoms of a trigeminal nerve affection. As surgical treatment we favour fenestration and cyst wall resection.

Adult↗

PubMed2002

In vitro reconstructed human epithelia reveal contributions of Candida albicans EFG1 and CPH1 to adhesion and invasion.

The individual and synergistic contributions of two transcription factors, EFG1 and CPH1, have been characterized with regard to adhesion to, and invasion of, human epithelia by Candida albicans. For this purpose two in vitro reconstructed tissue models were developed. A multi-layered model of human epidermis was used to simulate superficial infections of the skin, whereas a reconstructed human intestinal model was used to mimic the first steps of systemic infections. It was shown that C. albicans deleted for both transcription factors CPH1 and EFG1, in contrast to the congenic clinical isolate Sc5314, was neither able to adhere to, nor to penetrate, either of the model systems. A strain deleted for EFG1 alone showed significant reduction in adhesion and was not able to penetrate through the stratum corneum. However, strains deleted for CPH1 showed phenotypes paralleling the phenotypes of the clinical isolate Sc5314. Using different types of multi-layered human tissues reconstructed in vitro the individual contributions of Efg1p and Cph1p to two important virulence factors of C. albicans, namely adhesion and invasion, could be defined.

Candida albicans↗

PubMed2001

Preclinical protocol for in vivo selection of hematopoietic stem cells corrected by gene therapy in Fanconi anemia group C.

Fanconi anemia (FA) is an autosomal recessive disorder characterized by birth defects, increased incidence of malignancy, progressive bone marrow failure, and cellular hypersensitivity to DNA cross-linking agents. Bone marrow transplantation is therapeutic and therefore FA is a candidate disease for hematopoietic gene therapy. We have previously used mitomycin C (MMC) to achieve in vivo selection of wild-type hematopoietic stem cells (HSC) transplanted into FANCC knockout mice. However, clinical application of MMC in human FA gene therapy is unlikely because of its unknown toxicity profile in human FA patients. In contrast, cyclophosphamide (CPA) and gamma-irradiation (IR) are already in use with human FA patients and we therefore tested these regimens for their ability to achieve selection of genetically corrected HSCs in vivo. We found that nonmyeloablative doses of CPA or IR or combinations of CPA + IR were highly efficient at achieving in vivo selection of transplanted wild-type HSC. Furthermore, this nontoxic regimen also selected FANCC-mutant HSC corrected by ex vivo retroviral gene therapy. We suggest those nontoxic doses of CPA and/or IR could also be used to enhance gene therapy in human FA patients.

3T3 Cells↗

PubMed2001

Headless flies generated by developmental pathway interference.

Ectopic expression of transcription factors in eye-antennal discs of Drosophila strongly interferes with their developmental program. Early ectopic expression in embryonic discs interferes with the developmental pathway primed by Eyeless and generates headless flies, which suggests that Eyeless is necessary for initiating cell proliferation and development of both the eye and antennal disc. Interference occurs through a block in the cell cycle that for some ectopic transcription factors is overcome by D-CycE or D-Myc. Late ectopic expression in cone cell precursors interferes with their differentiation. We propose that this developmental pathway interference is a general surveillance mechanism that eliminates most aberrations in the genetic program during development and evolution, and thus seriously restricts the pathways that evolution may take.

Animals↗

PubMed2001

Multiple protein functions of paired in Drosophila development and their conservation in the Gooseberry and Pax3 homologs.

The Drosophila segmentation gene paired, whose product is homologous to the Drosophila Gooseberry and mammalian Pax3 proteins, has three general functions: proper development of the larval cuticle, survival to adulthood and male fertility. Both DNA-binding domains, the conserved N-terminal paired-domain and prd-type homeodomain, are required within the same molecule for all general paired functions, whereas a conserved His-Pro repeat located near its C terminus is a transactivation domain potentiating these functions. The C-terminal moiety of Paired includes two additional functional motifs: one, also present in Gooseberry and Pax3, is required for segmentation and cuticle development; the other, retained only in Gooseberry, is necessary for survival. The male fertility function, which cannot be replaced by Gooseberry and Pax3, is specified by the conserved N-terminal rather than the divergent C-terminal moiety of Paired. We conclude that the functional diversification of paired, gooseberry and Pax3, primarily determined by variations in their enhancers, is modified by adaptations of their coding regions as a necessary consequence of their newly acquired spatiotemporal expression.

Amino Acid Motifs↗

PubMed2001

Measurement of the depth distribution of average LET and absorbed dose inside a water-filled phantom on board space station MIR.

The Atominstitute of the Austrian Universities developed the HTR-method for determination of absorbed dose and "averaged" linear energy transfer (LET) in mixed radiation fields. The method was applied with great success during several space missions (e.g. STS-60, STS-63, BION-10 and BION-11) and on space station MIR in the past 10 years. It utilises the changes of peak height ratios in LiF thermoluminescent glowcurves in dependence on the LET. Due to the small size of these dosemeters the HTR-method can be used also for measurements inside tissue equivalent phantoms. A water filled phantom with a diameter of 35 cm containing four channels where dosemeters can be exposed in different depths was developed by the Institute for Biomedical Problems. This opens the possibility to measure the depth distribution of the average LET and the dose equivalent simultaneously. During phase 1 dosemeters were exposed for 271 days (05.1997-02.1998) in 6 different depths inside the phantom, which was positioned in the commander cabin. In phase 2 dosemeters were exposed in 2 channels in 6 different depths for 102 days (05.1998-08.1998) in the board engineer cabin, following an exposure in different channels in 3 different depths for 199 days (08.1998- 02.1999) in the Modul KWANT 2.

Humans↗

PubMed2000

Combinatorial signaling in the specification of unique cell fates.

How multifunctional signals combine to specify unique cell fates during pattern formation is not well understood. Here, we demonstrate that together with the transcription factor Lozenge, the nuclear effectors of the EGFR and Notch signaling pathways directly regulate D-Pax2 transcription in cone cells of the Drosophila eye disc. Moreover, the specificity of D-Pax2 expression can be altered upon genetic manipulation of these inputs. Thus, a relatively small number of temporally and spatially controlled signals received by a set of pluripotent cells can create the unique combinations of activated transcription factors required to regulate target genes and ultimately specify distinct cell fates within this group. We expect that similar mechanisms may specify pattern formation in vertebrate developmental systems that involve intercellular communication.

Animals↗

PubMed2000

Drosophila female sexual behavior induced by sterile males showing copulation complementation.

Females of most animal species are usually inseminated by more than one male, which allows sperm from different males to compete for fertilization. To prevent invasion of sperm from other males, Drosophila males elicit a rejection behavior in their mates after copulation. Using paired mutant males that, for the lack of accessory glands, are sterile, we show that this rejection behavior is induced exclusively by the secreted accessory gland products transferred to the female during copulation. Moreover, the activities of sperm and accessory gland products are complementary and interdependent: both sperm fertility and rejection behavior depend on accessory gland products whose prolonged activities, in turn, require the presence of sperm. Fertility of sperm from paired males can be restored by accessory gland products of spermless males in "copulation complementation" experiments. Our observations may have important implications for the role of sexual behavior in evolution and for the treatment of male sexual dysfunction in humans.

Animals↗

PubMed2000

Correlation of the LET-dependent TL-response of LIF:Mg,Ti TL-dosemeters and gentoxic endpoints after proton irradiation.

The high temperature ratio (HTR) method using LiF:Mg,Ti thermoluminescent dosemeters allows in addition to the measurement of absorbed dose, the evaluation of the biological effectiveness of radiation. In order to analyse the correlation of the measured parameter HTR and gentoxic endpoints irradiation of cell cultures and TLDs were performed in a 62 MeV proton beam. The gentoxic effects respectively the relative biological effectiveness RBE, show an excellent correlation with the HTR due to a similar dose and LET-dependent behaviour.

Animals↗

PubMed2000

Posttranscriptional regulation of smoothened is part of a self-correcting mechanism in the Hedgehog signaling system.

Hedgehog signaling, mediated through its Patched-Smoothened receptor complex, is essential for pattern formation in animal development. Activating mutations within Smoothened have been associated with basal cell carcinoma, suggesting that smoothened is a protooncogene. Thus, regulation of Smoothened levels might be critical for normal development. We show that Smoothened protein levels in Drosophila embryos are regulated posttranscriptionally by a mechanism dependent on Hedgehog signaling but not on its nuclear effector Cubitus interruptus. Hedgehog signaling upregulates Smoothened levels, which are otherwise downregulated by Patched. Demonstrating properties of a self-correcting system, the Hedgehog signaling pathway adjusts the concentrations of Smoothened and Patched to each other and to that of the Hedgehog signal, which ensures that activation of Hedgehog target genes by Smoothened signaling becomes strictly dependent on Hedgehog.

Animals↗

PubMed2000

Expression of ZntA, a zinc-transporting P1-type ATPase, is specifically regulated by zinc and cadmium.

All cells have developed various mechanisms to regulate precisely the availability of important micronutrients such as zinc and copper; in many cells, this regulation is mediated by P1-type ATPases. Most of the P1-ATPases have been described very recently, and little is known about their molecular mechanism and regulation. Here, we demonstrate that the expression of ZntA, a Zn,Cd-transporting P-type ATPase of Escherichia coli, is specifically regulated by the transported cations, cadmium and zinc. Nickel, cobalt, and copper did not induce the expression of ZntA, even when present at concentrations as high as 0.6-1 mM. The effect of zinc and cadmium on the ZntA expression is concentration dependent, the apparent Km for Cd (19 microM) being markedly lower than that for Zn (100 microM). This metal selectivity is opposite to the known metal selectivity of transport by ZntA. Thus, we speculate that, to maintain zinc concentrations in the cell in the presence of cadmium, ZntA probably interacts with other proteins that modulate the ZntA selectivity towards transported cations.

Adenosine Triphosphatases↗

PubMed2000

T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis.

Clinical and histologic similarities between various eczematous disorders point to a common efferent pathway. We demonstrate here that activated T cells infiltrating the skin in atopic dermatitis (AD) and allergic contact dermatitis (ACD) induce keratinocyte (KC) apoptosis. KCs normally express low levels of Fas receptor (FasR) that can be substantially enhanced by the presence of IFN-gamma. KCs are rendered susceptible to apoptosis by IFN-gamma when FasR numbers reach a threshold of approximately 40,000 per KC. Subsequently, KCs undergo apoptosis induced by anti-FasR mAb's, soluble Fas ligand, supernatants from activated T cells, or direct contact between T cells and KCs. Apoptotic KCs show typical DNA fragmentation and membrane phosphatidylserine expression. KC apoptosis was demonstrated in situ in lesional skin affected by AD, ACD, and patch tests. Using numerous cytokines and anti-cytokine neutralizing mAb's, we found no evidence that cytokines other than IFN-gamma participate in this process. In addition, apoptosis-inducing pathways other than FasR triggering were ruled out by blocking T cell-induced KC apoptosis by caspase inhibitors and soluble Fas-Fc protein. Responses of normal human skin and cultured skin equivalents to activated T cells demonstrated that KC apoptosis caused by skin-infiltrating T cells is a key event in the pathogenesis of eczematous dermatitis.

Apoptosis↗

PubMed2000

Regulation of Drosophila wing vein patterning: net encodes a bHLH protein repressing rhomboid and is repressed by rhomboid-dependent Egfr signalling.

The stereotyped pattern of veins in the Drosophila wing is generated in response to local EGF signalling. Mutations in the rhomboid (rho) gene, which encodes a sevenpass membrane protein required to enhance signalling transmitted by the EGF receptor (Egfr), inhibit vein development and disrupt the vein pattern. By contrast, net mutations produce ectopic veins in intervein regions. We have cloned the net gene and show that it encodes a basic HLH protein that probably acts as a transcriptional repressor. net and rho are expressed in mutually exclusive patterns during the development of the wing imaginal disc. Lack of net activity causes rho expression to expand, and vice versa. Furthermore, ectopic expression of net or rho results in their mutual repression and thus suppresses vein formation or generates tube-like wings composed of vein-like tissue. Egfr signalling and net exert mutually antagonising activities during the specification of vein versus intervein fate. While Egfr signalling represses net transcription, net exhibits a two-tiered control by repressing rho transcription and interfering with Egfr signalling downstream of Rho. Our results further suggest that net is required to maintain intervein development by restricting Egfr signalling, which promotes vein development, to the Net-free vein regions of the wing disc.

Amino Acid Sequence↗

PubMed1999

Measurements of the equivalent dose in aircraft with TLDS.

For measurements of the equivalent dose of the mixed radiation fields in aircraft many different measuring devices are usually necessary for consideration of the different components of the radiation field. The possibility is discussed of using thermoluminescence dosemeters (TLDS) for determination of absorbed dose and average LET of this complex radiation field in aircraft. The HTR method, developed for determination of the equivalent dose in spacecraft, enables the measurement of the average LET in addition to the absorbed dose. Furthermore, a rem counter based on TLDs and a modified pair method (TLD-600, TLD-700) was used for determination of the absorbed dose due to the neutron component. Using small TLD crystals it is possible to obtain the depth distribution of absorbed dose and average LET by exposing TLDs in Bonner spheres with different diameters. The results indicate that the standards for determination of the effective dose may not be applicable in these mixed radiation fields in aircraft.

Aircraft↗

PubMed1999

Determination of the absorbed dose and the average LET of space radiation in dependence on shielding conditions.

The HTR method, developed for determination of absorbed dose and average LET of mixed radiation fields in space, was applied during several space missions on space station MIR, space shuttles and satellites. The method utilises the changes of peak height ratios in the glow curves in dependence on the linear energy transfer LET. Due to the small size of the dosemeters the evaluation of the variation of absorbed dose and average LET in dependence on the position of the dosemeters inside the space station is possible. The dose and LET distribution was determined during the experiment ADLET where dosemeters were exposed in two positions with different shielding conditions and during two following experiments (MIR-95, MIR-96) using six positions inside the space station. The results were compared with the shielding conditions of the positions. Calculations of the absorbed dose were carried out for comparison. Results have shown that the average LET increases with increasing absorbing thickness while the absorbed dose decreases.

Cosmic Radiation↗

PubMed1999

An essential role for the Drosophila Pax2 homolog in the differentiation of adult sensory organs.

The adult peripheral nervous system of Drosophila includes a complex array of mechanosensory organs (bristles) that cover much of the body surface of the fly. The four cells (shaft, socket, sheath, and neuron) which compose each of these organs adopt distinct fates as a result of cell-cell signaling via the Notch (N) pathway. However, the specific mechanisms by which these cells execute their conferred fates are not well understood. Here we show that D-Pax2, the Drosophila homolog of the vertebrate Pax2 gene, has an essential role in the differentiation of the shaft cell. In flies bearing strong loss-of-function mutations in the shaven function of D-Pax2, shaft structures specifically fail to develop. Consistent with this, we find that D-Pax2 protein is expressed in all cells of the bristle lineage during the mitotic (cell fate specification) phase of bristle development, but becomes sharply restricted to the shaft and sheath cells in the post-mitotic (differentiative) phase. Two lines of evidence described here indicate that D-Pax2 expression and function is at least in part downstream of cell fate specification mechanisms such as N signaling. First, we find that the lack of late D-Pax2 expression in the socket cell (the sister of the shaft cell) is controlled by N pathway activity; second, we find that loss of D-Pax2 function is epistatic to the socket-to-shaft cell fate transformation caused by reduced N signaling. Finally, we show that misexpression of D-Pax2 is sufficient to induce the production of ectopic shaft structures. From these results, we propose that D-Pax2 is a high-level transcriptional regulator of the shaft cell differentiation program, and acts downstream of the N signaling pathway as a specific link between cell fate determination and cell differentiation in the bristle lineage.

Alleles↗

PubMed1999

double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs.

We have isolated the discs overgrown gene of Drosophila and shown that it encodes a homolog of the Casein kinase I(delta)/(epsilon) subfamily and is identical to the double-time gene. However, in contrast to the weak double-time alleles, which appear to affect only the circadian rhythm, discs overgrown alleles, including bona fide null alleles, show strong effects on cell survival and growth control in imaginal discs. Analysis of their phenotypes and molecular lesions suggests that the Discs overgrown protein is a crucial component in the mechanism that links cell survival during proliferation to growth arrest in imaginal discs. This work provides the first analysis in a multicellular organism of Casein kinase I(delta)/(epsilon) functions necessary for survival. Since the amino acid sequences and three-dimensional structures of Casein kinase I(delta)/(epsilon) enzymes are highly conserved, the results suggest that these proteins may also function in controlling cell growth and survival in other organisms.

Amino Acid Sequence↗

PubMed1998

Identification of a novel transcription regulator from Proteus mirabilis, PMTR, revealed a possible role of YJAI protein in balancing zinc in Escherichia coli.

Zinc is an essential trace element required for structural integrity and functional activity of numerous proteins, yet mechanisms by which cells regulate zinc concentration are poorly understood. Here, we identified a gene from Proteus mirabilis that encodes a 135-amino acid residue protein, PMTR (P. mirabilis transcription regulator), a new member of the MerR family of transcription activators. Transformation of Escherichia coli with PMTR-carrying vectors specifically increases cell tolerance to zinc, suggesting the role of PMTR in zinc homeostasis. In response to zinc, PMTR-containing cells robustly accumulate a 12-kDa protein, the amount of which correlates with the cells' ability to grow at high zinc concentrations. The 12-kDa protein is not induced in the presence of Ni2+, Co2+, Cd2+, Mn2+, or Fe2+, indicating that the PMTR-dependent expression of the 12-kDa protein is specifically regulated by zinc. The 12-kDa protein was identified as the C-terminal fragment of E. coli protein YJAI, and was shown to contain two zinc-binding motifs. Metal-affinity chromatography and 65Zn blotting assay confirmed the ability of the 12-kDa protein to bind zinc specifically (zinc > cobalt >> cadmium). We propose that YJAI is an important component of the zinc-balancing mechanism in E. coli, the up-regulation of which with PMTR results in an increased tolerance to zinc.

Amino Acid Sequence↗