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Biomedical subjects

S Krauss

Publications and source records attributed to S Krauss.

At least 55 records · Page 3Linked to original sources
PubMed1998

Conservation of BF-1 expression in amphioxus and zebrafish suggests evolutionary ancestry of anterior cell types that contribute to the vertebrate telencephalon.

The forkhead domain containing transcription factor BF-1 has been shown to play a major role in the correct development of the cerebral hemispheres in the mouse. BF-1 orthologs have been isolated from zebrafish and the cephalocordate amphioxus. In both species, BF-1 is expressed in the anterior neural tube. In zebrafish zBF-1 expression is restricted to anterior portions of the otic vesicle and to the presumptive telencephalon. In amphioxus AmphiBF-1 is transiently seen in the frontal part of the first somite and, at 3 days of development, in a small number of cells in the cerebral vesicle (cv). The anterior expression of BF-1 in chordates and vertebrates and of slp-1/2 in Drosophila suggests that BF-1 is crucial for an evolutionarily conserved specification of anterior neuronal cell types.

Amino Acid Sequence↗
PubMed1998

Zebrafish contains two pax6 genes involved in eye development.

The Pax6 genes of both vertebrates and invertebrates are expressed in the developing eye and in the central nervous system. These genes encode transcription factors with two DNA-binding domains, an N-terminal paired domain and a homeodomain separated by a flexible linker region. Ectopic eye structures are obtained upon targeted expression of Drosophila, squid, ascidian or mouse Pax6 genes in various imaginal disc primordia of Drosophila. We have previously cloned a Pax6 cDNA from zebrafish. Here we report the cloning of a novel Pax6 homolog from zebrafish denoted Pax6.2. The coding sequences of the two genes show 82% identity whereas the deduced amino acid sequences are 95% identical with complete conservation of the paired- and homeodomains. The embryonic expression patterns of Pax6.1 and Pax6.2 reveal both overlapping and discrete expression domains suggesting a division of labor between these two very similar gene products during development of brain and eye structures. Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. Both Pax6.1 and Pax6.2 are able to induce ectopic eyes in Drosophila, while Pax2 is not, suggesting that eye induction is not a general feature of Pax family genes but a distinct characteristic of Pax6 and its direct homologs. Attempts to detect Pax6. 2 homologs in chick, mice or humans proved unsuccessful suggesting that this gene either was lost during evolution of higher vertebrates or, more likely, arose as part of a larger scale duplication of chromosome segments occurring in the zebrafish lineage.

Amino Acid Sequence↗
PubMed1998

A phase II study of 9-aminocamptothecin in advanced non-small-cell lung cancer.

BACKGROUND: 9-Aminocamptothecin (9-AC) is a synthetic analogue of camptothecin. Phase I studies, identified the maximum tolerated dose as 1416 micrograms/m2/day x 3 as continuous intravenous infusion (CVI) with dose-limiting neutropenia. PATIENTS AND METHODS: Eligible patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) with measurable disease. Patients were initially treated at 1416 micrograms/m2/d x 3 by CVI followed by granulocyte-colony stimulating factor (G-CSF) support. This dose was decreased to 1100 micrograms/m2/d after the first 13 patients. Cycles were repeated every 14 days until tumor progression. RESULTS: Fifty-eight patients were treated, thirteen at 1416 micrograms/m2/d and 45 at 1100 micrograms/m2/d. Fifty percent had adenocarcinoma and 17% squamous cell carcinoma. Seventy-one percent had stage IV disease. Five patients had a partial response (response duration 9-28 weeks) for an overall response rate of 8.6%, (95% confidence intervals (CI): 2.9%-19%). Median time to progression was 2.3 months and the median survival for the entire study population 5.4 months with a one-year survival rate of 30%. The one-year survival rate for 27 patients who received second line chemotherapy was 56.7%. Toxicities at 1416 micrograms/m2/d included grade 4 neutropenia and thrombocytopenia in six and five of 13 patients, respectively; at 1100 micrograms/m2/d these toxicities were observed in 12 and three of 45 patients, respectively. CONCLUSION: 9-AC has modest single-agent activity in previously untreated NSCLC. Its further evaluation at the dose and schedule employed in this study does not seem indicated. Exploration of more prolonged administration schedules may be warranted.

Aged↗
PubMed1998

Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse.

During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.

Abnormalities, Multiple↗
PubMed1998

Molecular basis for the generation in pigs of influenza A viruses with pandemic potential.

Genetic and biologic observations suggest that pigs may serve as "mixing vessels" for the generation of human-avian influenza A virus reassortants, similar to those responsible for the 1957 and 1968 pandemics. Here we demonstrate a structural basis for this hypothesis. Cell surface receptors for both human and avian influenza viruses were identified in the pig trachea, providing a milieu conducive to viral replication and genetic reassortment. Surprisingly, with continued replication, some avian-like swine viruses acquired the ability to recognize human virus receptors, raising the possibility of their direct transmission to human populations. These findings help to explain the emergence of pandemic influenza viruses and support the need for continued surveillance of swine for viruses carrying avian virus genes.

Adaptation, Biological↗
PubMed1997

Cloning and expression of three members of the zebrafish Bmp family: Bmp2a, Bmp2b and Bmp4.

In vertebrates, Bmps (bone morphogenetic proteins) play critical roles in establishing the basic embryonic body plan and are involved in the development of a large variety of organs and tissues. To study the evolution of Bmps, we isolated cDNAs for three members of the zebrafish Bmp gene family: Bmp2a, Bmp2b and Bmp4. The deduced amino acid sequences of Bmp2a and Bmp4 consist of 386 and 400 aa, respectively and show high homologies to their counterparts in mouse, chick and Xenopus. The deduced Bmp2b aa sequence consists of 411 aa and the mature protein shows 88% and 86% identities to zebrafish Bmp2a and Bmp4, respectively. The expression of the mRNA of these three genes has been analyzed by whole mount in situ hybridization and RT-PCR. Areas of zebrafish Bmp2 and Bmp4 expression suggest evolutionary conserved mechanisms of Bmp2/4 dependent differentiation between lower and higher vertebrates.

Amino Acid Sequence↗
PubMed1997

Methylprednisolone inhibits uptake of Ca2+ and Na+ ions into concanavalin A-stimulated thymocytes.

The glucocorticoid drug methylprednisolone inhibits respiration in concanavalin A-stimulated rat thymocytes at concentrations that are relevant to its acute clinical efficacy against autoimmune diseases and spinal cord injury. Methylprednisolone affects several processes, including ion cycling, substrate oxidation reactions and RNA/DNA synthesis. The inhibition of respiration used to drive ATP-consuming cycles of Ca2+ and Na+ ions across the plasma membrane has been proposed to be either primary or secondary to restriction of cellular ATP supply. By comparing the effects of methylprednisolone with those of myxothiazol, an inhibitor of the mitochondrial electron transport chain, we show that the effects of methylprednisolone on Ca2+ and Na+ cycling are primary. We propose that methylprednisolone acts by affecting membrane properties to inhibit Ca2+ and Na+ uptake across the plasma membrane and to increase H+ uptake across the mitochondrial membrane, and that other effects are secondary.

Adenosine Triphosphate↗
PubMed1997

Continued evolution of H1N1 and H3N2 influenza viruses in pigs in Italy.

Swine influenza viruses possessing avian genes were first detected in Europe in 1979 (Scholtissek et al., 1983, Virology, 129, 521-523) and continue to circulate in pigs in that region of the world. To characterize the molecular epidemiology of swine influenza viruses currently circulating in Europe, we used dot-blot hybridization and sequence analysis to determine the origin of the genes encoding the nonsurface proteins ("internal" genes) of 10 H1N1 and 11 H3N2 swine influenza viruses isolated in Italy between 1992 and 1995. All of the 126 genes examined were of avian origin; thus the currently circulating H3N2 strains which possess A/Port Chalmers/1/73-like surface glycoproteins appear to be descendants of the reassortant human-avian viruses that emerged between 1983 and 1985 in Italy. Sequence analysis of matrix (M), nonstructural, and nucleoprotein genes, as well as phylogenetic analysis of M gene showed that the H1N1 and H3N2 viruses from the pigs were closely related to recent isolates of the avian-like swine H1N1 influenza strain currently circulating in northern Europe and were distinguishable from the genes of viruses isolated from European swine in 1979. To evaluate the frequency of transmission of swine H1N1 and H3N2 viruses to man, we tested 123 human sera for hemagglutination-inhibiting antibodies against avian and mammalian H1N1 and H3N2 virus strains. Our findings indicate that swine influenza viruses possessing A/Port Chalmers/1/73-like hemagglutinin may have transmitted to approximately 20% of young persons under 20 years of age who had contact with pigs. Thus, H3N2 swine viruses, possibly possessing avian-derived internal genes, may be entering humans more often than was previously thought. We strongly recommend that pigs be regularly monitored as a potential early warning system for detection of future pandemic strains.

Adult↗
PubMed1997

Quantitative imaging study of extent of surgical resection and prognosis of malignant astrocytomas.

OBJECTIVE: This study used quantitative radiological imaging to determine the effect of surgical resection on postoperative survival of patients with malignant astrocytomas. Previous studies relied on the surgeons' impressions of the amount of tumor removed, which is a less reliable measure of the extent of resection. METHODS: Information concerning possible prognostic factors was collected for 75 patients undergoing magnetic resonance imaging or computed tomography preoperatively and within 10 days postoperatively. Image analysis of the neuroradiological studies was conducted to quantify pre- and postoperative total tumor volumes and enhancing volumes. Univariate and multivariate proportional hazards models were used to analyze the regression of survival regarding 22 covariates that might affect survival. The covariates that were entered included age, gender, tumor grade, cumulative radiation dose, chemotherapy, seizures as a first symptom, Karnofsky performance status at presentation, pre- and postoperative total and enhancing tumor volumes, ratio of pre- to postoperative total and enhancing tumor volumes, tumor location, surgeon's impression of the degree of resection, and subsequent surgery. RESULTS: There were 23 patients with anaplastic astrocytomas and 52 with glioblastomas multiforme. The estimated mean survival time was 27 months for patients undergoing gross total resection, 33 months for subtotal resection, and 13 months for open or stereotactic biopsy. Five factors that were significant predictors of survival in multivariate analysis were tumor grade, age, Karnofsky performance status, radiation dose, and postoperative complications (P < 0.05). In univariate analysis, tumor grade, radiation dose, age, Karnofsky status, complications, presence of enhancing tumor in postoperative imaging, and postoperative volume of enhancing tumor were significantly associated with survival (P < 0.05). CONCLUSION: We conclude that the most important prognostic factors affecting survival of patients with anaplastic astrocytomas and glioblastomas multiforme are tumor grade, age, preoperative performance status, and radiation therapy. Postoperative complications adversely affect survival. Aggressive surgical resection did not impart a significant increase in survival time. Surgical resection may improve survival, but its importance is less than that of other factors and may be demonstrable only by larger studies.

Adult↗
PubMed1996

Zebrafish Pax9 encodes two proteins with distinct C-terminal transactivating domains of different potency negatively regulated by adjacent N-terminal sequences.

We describe the isolation of cDNA clones for zebrafish Pax9. Pax9 expression was initiated at the end of the segmentation period in mesenchymal sclerotome cells on both sides of the notochord similarly to the corresponding mouse and chick genes. Two transcripts, Pax9a and -b, are generated by alternative splicing. The gene contains 4 exons with exon 3 being included in the Pax9a transcript and spliced out in the Pax9b transcript. The Pax9a and -b proteins are identical for 212 amino acids from the N terminus but contain distinct C-terminal regions of 131 and 58 amino acids, respectively. The paired domain of Pax9 displayed a binding-site specificity distinct from Pax6 but similar to Pax1 and -2. Both Pax9a and -b activated a promoter containing a paired domain binding site. However, this activation was observed when low amounts of Pax9 expression vectors were used. Higher amounts led to a sharp decrease in the activation and even turned into repression. Both the distinct C-terminal regions of Pax9a and -b harbored transcriptional activating domains of different potency not revealed in the context of the full-length proteins due to a negative influence of the N-terminal region including the paired domain.

Alternative Splicing↗
PubMed1996

Flux control exerted by overt carnitine palmitoyltransferase over palmitoyl-CoA oxidation and ketogenesis is lower in suckling than in adult rats.

We examined the potential of overt carnitine palmitoyltransferase (CPT I) to control the hepatic catabolism of palmitoyl-CoA in suckling and adult rats, using a conceptually simplified model of fatty acid oxidation and ketogenesis. By applying top-down control analysis, we quantified the control exerted by CPT I over total carbon flux from palmitoyl-CoA to ketone bodies and carbon dioxide. Our results show that in both suckling and adult rat, CPT I exerts very significant control over the pathways under investigation. However, under the sets of conditions we studied, less control is exerted by CPT I over total carbon flux in mitochondria isolated from suckling rats than in those isolated from adult rats. Furthermore the flux control coefficient of CPT I changes with malonyl-CoA concentration and ATP turnover rate.

Animals↗
PubMed1996

Regulation and control in complex, dynamic metabolic systems: experimental application of the top-down approaches of metabolic control analysis to fatty acid oxidation and ketogenesis.

Metabolic control analysis has provided experimental tools and a precise language to understand and to describe regulation and control quantitatively in complex, dynamic metabolic systems. The top-down approaches of control analysis reduce and simplify the experiments required to analyse: (1) the potential (group control coefficients) of system parameters (blocks of reactions) to control system variables (fluxes, metabolite concentrations); (2) the sensitivity (group elasticity coefficients) of those blocks of reactions to the action of direct and/or indirect effectors and (3) the regulation of system variables, fluxes through blocks of reactions (partial response coefficients) or through the entire pathway (group response coefficients), by internal or external effectors. Although metabolic control analysis expresses regulation and control in terms of response or control coefficients, which are mathematically derived and have numerical values, the two terms are mathematically indistinguishable. In this paper, we define regulation and control as a consequence of hierarchy and not of mathematical function and analyse a conceptually simplified experimental system to demonstrate our distinction.

Animals↗
PubMed1996

Activation of T cells by the ragged tail of MHC class II-presented peptides of the measles virus fusion protein.

The efficient and sustained immune response of an antigen requires T cell epitopes, capable of inducing a long lasting T cell memory. To detect T cell epitopes of the measles virus fusion protein (MV-F), the proliferation of lymphocytes from late convalescent donors in response to overlapping pentadecapeptides covering the whole protein sequence was studied. Three major immunodominant regions (F51-70, F121-135 and F211-225) containing promiscuous peptides induce proliferation in peripheral blood lymphocytes in approximately 50% of the donors. Potential DR1-restricted epitopes were mapped using an MHC competition binding assay. Both the proliferation and the binding data identified a DR1-restricted T cell epitope (F51-65). Contact sites of the peptide HQSLVIKLMPNITLL with MHC were characterized using substitution analogs. Alanine substitutions at most positions did not interfere with F51-65 binding. These analogs were therefore useful for studying the residues which were recognized by the TCR of MV- and F51-induced T cells lines. In addition to amino acid residues of the core of peptide F51-65 both the C-terminal and the N-terminal amino acids were essential for T cell interaction. Since peptides presented by class II molecules vary in length, these findings suggest that residues of the ragged tail are important for T cell activation. It is speculated that in late convalescent donors the length of the flanking sequence of MHC II-restricted peptides may play a role in controlling the heterogeneity of MV-specific T cell clones recruited as T helper/memory cells.

Adult↗
PubMed1996

The non-haem chloroperoxidase from Pseudomonas fluorescens and its relationship to pyrrolnitrin biosynthesis.

The non-haem chloroperoxidase gene (cpoF) from the pyrrolnitrin producer Pseudomonas fluorescens BL914 was cloned using an oligonucleotide derived from part of the N-terminal amino acid sequence of chloroperoxidase (CPO-P) from Pseudomonas pyrrocina as a probe. Based on the overexpression of cpoF in Escherichia coli and the stability of CPO-F against higher temperatures and proteases, the enzyme was purified to homogeneity. Partial characterization of the enzyme showed that it belongs to the class of bacterial non-haem CPOs. To investigate the role of CPO-F in pyrrolnitrin biosynthesis, the cpoF gene was inactivated by insertion of a kanamycin cassette. Exchange of the chromosomal cpoF gene against the disrupted copy had no influence on pyrrolnitrin production demonstrating that CPO-F was not involved in pyrrolnitrin biosynthesis.

Chloride Peroxidase↗
PubMed1996

Emergence of avian H1N1 influenza viruses in pigs in China.

Avian influenza A viruses from Asia are recognized as the source of genes that reassorted with human viral genes to generate the Asian/57 (H2N2) and Hong Kong/68 (H3N2) pandemic strains earlier in this century. Here we report the genetic analysis of avian influenza A H1N1 viruses recently isolated from pigs in southern China, a host suspected to generate new pandemic strains through gene reassortment events. Each of the eight gene segments was of avian origin. Phylogenetic analysis indicates that these genes form an Asian sublineage of the Eurasian avian lineage, suggesting that these viruses are an independent introduction into pigs in Asia. The presence of avian influenza viruses in pigs in China places them in an optimal position for transmission to humans and may serve as an early warning of the emergence of the next human influenza virus pandemic.

Animals↗