Showing papers by "University of Cologne published in 1995"
TL;DR: A method of gene targeting that allows the inducible inactivation of a target gene in mice is presented, which uses an interferon-responsive promoter to control the expression of Cre recombinase.
Abstract: A method of gene targeting that allows the inducible inactivation of a target gene in mice is presented The method uses an interferon-responsive promoter to control the expression of Cre recombinase Here, Cre was used to delete a segment of the DNA polymerase beta gene flanked by IoxP recombinase recognition sites Deletion was complete in liver and nearly complete in lymphocytes within a few days, whereas partial deletion was obtained in other tissues This method can be used for the inducible inactivation of any other gene in vivo
1,918 citations
TL;DR: In this article, the authors present explicit models for a symmetry breakdown in the cases of the Weyl (or homothetic) group, the SL(4, R), or the GL(4-R) covering subgroup.
1,474 citations
TL;DR: The magnetic field experiment on WIND will provide data for studies of a broad range of scales of structures and fluctuation characteristics of the interplanetary magnetic field throughout the mission, and, where appropriate, relate them to the statics and dynamics of the magnetosphere.
Abstract: The magnetic field experiment on WIND will provide data for studies of a broad range of scales of structures and fluctuation characteristics of the interplanetary magnetic field throughout the mission, and, where appropriate, relate them to the statics and dynamics of the magnetosphere. The basic instrument of the Magnetic Field Investigation (MFI) is a boom-mounted dual triaxial fluxgate magnetometer and associated electronics. The dual configuration provides redundancy and also permits accurate removal of the dipolar portion of the spacecraft magnetic field. The instrument provides (1) near real-time data at nominally one vector per 92 s as key parameter data for broad dissemination, (2) rapid data at 10.9 vectors s−1 for standard analysis, and (3) occasionally, snapshot (SS) memory data and Fast Fourier Transform data (FFT), both based on 44 vectors s−1. These measurements will be precise (0.025%), accurate, ultra-sensitive (0.008 nT/step quantization), and where the sensor noise level is <0.006 nT r.m.s. for 0–10 Hz. The digital processing unit utilizes a 12-bit microprocessor controlled analogue-to-digital converter. The instrument features a very wide dynamic range of measurement capability, from ±4 nT up to ±65 536 nT per axis in eight discrete ranges. (The upper range permits complete testing in the Earth's field.) In the FTT mode power spectral density elements are transmitted to the ground as fast as once every 23 s (high rate), and 2.7 min of SS memory time series data, triggered automatically by pre-set command, requires typically about 5.1 hours for transmission. Standard data products are expected to be the following vector field averages: 0.0227-s (detail data from SS), 0.092 s (‘detail’ in standard mode), 3 s, 1 min, and 1 hour, in both GSE and GSM coordinates, as well as the FFT spectral elements. As has been our team's tradition, high instrument reliability is obtained by the use of fully redundant systems and extremely conservative designs. We plan studies of the solar wind: (1) as a collisionless plasma laboratory, at all time scales, macro, meso and micro, but concentrating on the kinetic scale, the highest time resolution of the instrument (=0.022 s), (2) as a consequence of solar energy and mass output, (3) as an external source of plasma that can couple mass, momentum, and energy to the Earth's magnetosphere, and (4) as it is modified as a consequence of its imbedded field interacting with the moon. Since the GEOTAIL Inboard Magnetometer (GIM), which is similar to the MFI instrument, was developed by members of our team, we provide a brief discussion of GIM related science objectives, along with MFI related science goals.
1,368 citations
TL;DR: The infected mutant mice developed a significantly stronger Thl type of immune response than the wild-type or heterozygous mice, and showed reduced nonspecific inflammatory response to carrageenin, and were resistant to lipopolysaccharide-induced mortality.
Abstract: NITRIC oxide (NO) is important in many biological functions1–5. It is generated from L-arginine by the enzyme NO synthase (NOS). The cytokine-inducible NOS (iNOS) is activated by several immunological stimuli, leading to the production of large quantities of NO which can be cytotoxic6. To define the biological role of iNOS further, we generated iNOS mutant mice. These are viable, fertile and without evident histopathological abnormalities. However, in contrast to wild-type and heterozygous mice, which are highly resistant to the protozoa parasite Leishmania major infection, mutant mice are uniformly susceptible. The infected mutant mice developed a significantly stronger Thl type of immune response than the wild-type or heterozygous mice. The mutant mice showed reduced nonspecific inflammatory response to carrageenin, and were resistant to lipopolysaccharide-induced mortality.
1,305 citations
1,287 citations
TL;DR: Low-grade primary gastric MALT lymphoma can completely regress after eradication of H pylori infection, however, longer follow-up is needed to clarify whether the remission is lasting.
953 citations
TL;DR: The results emphasise once again the marked efficacy and low rate of complications associated with oral and parenteral analgesic therapy as the mainstay of pain treatment in the palliative care of patients with adBANced cancer.
Abstract: This paper reports on the experience gained using World Health Organization Guidelines for cancer pain relief over a 10-year period in an anaesthesiology-based pain service associated with a palliative care programme. The course of treatment of 2118 patients was assessed prospectively over a period of 140,478 treatment days. Non-opioid analgesics (WHO step I) were used on 11%, weak opioids (WHO step II) on 31% and strong opioids (WHO step III) on 49% of treatment days. Administration was via the enteral route on 82% and parenterally on 9% of treatment days. On the remaining days, either spinally applied opioids (2%) or other treatments (6%) were utilised. Fifty-six percent of the patients were treated with morphine. Morphine dose escalation was observed in about one-half of the patients being cared for until death, whereas the other half had stable or decreasing doses over the course of treatment. Co-analgesics were administered on 37% of days, most often antidepressants (15%), anticonvulsants (13%) and corticosteroids (13%). Adjuvants to treat symptoms other than pain were prescribed on 79% of days, most commonly laxatives (42%), histamine-2-receptor antagonists (39%) and antiemetics (35%). In addition, palliative antineoplastic treatment was performed in 42%, nerve blocks in 8%, physiotherapy in 5%, psychotherapy in 3% and TENS in 3% of patients. A highly significant pain reduction was achieved within the 1st week of treatment (P < 0.001). Over the whole treatment period, good pain relief was reported in 76%, satisfactory efficacy in 12% and inadequate efficacy in 12% of patients. In the final days of life, 84% rated their pain as moderate or less, while 10% were unable to give a rating. Analgesics remained constantly effective in all 3 steps of the WHO ladder. Other clinical symptoms were likewise significantly reduced at 1 week after initial assessment, with the exception of neuropsychiatric symptoms. During the course of treatment, the latter were the major symptoms on 23% of days, followed by nausea (23%), constipation (23%) and anorexia (20%). Our results emphasise once again the marked efficacy and low rate of complications associated with oral and parenteral analgesic therapy as the mainstay of pain treatment in the palliative care of patients with advanced cancer. Wide dissemination of WHO guidelines among doctors and healthcare workers is thus necessary to effect a clear improvement in the treatment of the many patients suffering from cancer pain in the clinical and home setting.
950 citations
TL;DR: Evidence is presented to show that the insertion of crumbs into the plasma membrane is necessary and sufficient to confer apical character on a membrane domain, and to suggest that crumbs plays a key role in specifying the apical plasma membrane domain of ectodermal epithelial cells of Drosophila.
716 citations
TL;DR: CD 19 is crucial for both initial B-cell activation by T-cell-dependent antigens and the maturation and/or selection of the activated cells into the memory compartment, and an impairment in ligand-driven selection may also be responsible for the observation of a striking reduction in the B-l B- cell subset.
Abstract: CD19 is the hallmark differentiation antigen of the B lineage. Its early expression has implicated a role for CD19 during the antigen-independent phases of B-cell development, whereas in mature B cells CD19 can act synergistically with surface immunoglobulin to induce activation. We have generated CD19-deficient mice and found that development of conventional B cells is unperturbed. However, mature CD19-/- B cells show a profound deficiency in responding to protein antigens that require T-cell help. This is accompanied by a lack of germinal centre formation and affinity maturation of serum antibodies. Thus CD19 is crucial for both initial B-cell activation by T-cell-dependent antigens and the maturation and/or selection of the activated cells into the memory compartment. An impairment in ligand-driven selection may also be responsible for the observation of a striking reduction in the B-1 (formerly Ly-1) B-cell subset, thought to develop under the control of self-antigens and bacterial antigens (reviewed in ref. 2).
668 citations
TL;DR: No overall beneficial effect of corticosteroids in patients with sepsis or septic shock was observed; however, there is some evidence for a positive effect in Patients with Gram-negative septicemia.
Abstract: Objective The use of corticosteroids in patients with sepsis or septic shock has been controversial for many decades. Clinical studies have reported beneficial, as well as negative results. We conducted a meta-analysis to assess the clinical evidence and to evaluate treatment effects in specific sub
471 citations
TL;DR: Observations indicate that CD5 can influence the fate of developing thymocytes by acting as a negative regulator of TCR-mediated signal transduction.
Abstract: CD5 is a transmembrane protein that is expressed on the surface of T cells and a subset of B cells. The absence of CD5 rendered thymocytes hyperresponsive to stimulation through the T cell antigen receptor (TCR) in vitro. Selection of T cells expressing three distinct transgenic TCRs was also abnormal in CD5-deficient mice. These observations indicate that CD5 can influence the fate of developing thymocytes by acting as a negative regulator of TCR-mediated signal transduction.
TL;DR: This model describes single-lane traffic flow on a ring and generalizes the asymmetric exclusion process models and calculates the so-called fundamental diagrams (flow vs. density) for parallel dynamics by means of an improved mean-field approximation.
Abstract: We investigate a probabilistic cellular automaton model which has been introduced recently. This model describes single-lane traffic flow on a ring and generalizes the asymmetric exclusion process models. We study the equilibrium properties and calculate the so-called fundamental diagrams (flow versus density) for parallel dynamics. This is done numerically by computer simulations of the model and by means of an improved mean-field approximation which takes into account short-range correlations. For cars with a maximum velocity of 1, the simplest nontrivial approximation gives the exact result. For higher velocities, the analytical results, obtained by iterated application of the approximation scheme, are in excellent agreement with the numerical simulations.
TL;DR: It is reported that antigen receptor-mediated proliferative responses of B and T cells in vitro are severely reduced in the absence of Vav, and a direct link between the low proliferative response of VAV-deficient B andT cells and the reduced number of these cells in peripheral lymphoid organs of chimaeric mice is suggested.
Abstract: CROSSLINKING of B- or T-cell antigen receptors results in the rapid tyrosine phosphorylation of a number of proteins, including Vav, a protein expressed in cells of the haematopoietic system1–3. Vav contains an array of structural motifs that include Src-homology domains SH2/SH34 and regions of homology to the guanine-nucleotide-exchange protein Dbl, pleckstrin and protein kinase C (refs 5-9). Using the RAG-complementation approach10, we have analysed in vivo differentiation and in vitro responses of B-and T-lineage cells generated by injection of embryonic stem cells homozygous for a null mutation in the vav gene into blastocysts of RAG-1- or RAG-2-deficient mice. Here we report that antigen receptor-mediated proliferative responses of B and T cells in vitro are severely reduced in the absence of Vav. We also suggest a direct link between the low proliferative response of Vav-deficient B and T cells and the reduced number of these cells in peripheral lymphoid organs of chimaeric mice.
TL;DR: Findings provide evidence that in failing human myocardium caused by dilated cardiomyopathy, protein levels of SERCA II and phospholamban are unchanged even though mRNA levels for SERCAII and phosphoamban and theSERCA II function are reduced compared with nonfailing myocardia.
Abstract: Background The aim of the present study was to investigate whether Ca2+ uptake into the sarcoplasmic reticulum (SR) is altered in failing human myocardium resulting from dilated cardiomyopathy. Methods and Results Ca2+-ATPase (SERCA II) activity and Ca2+-dependent 45Ca2+ uptake (oxalate supported, steady state) in isolated vesicles from the SR (VSR) and in crude membrane preparations (CSR) (free Ca2+, 0.01 to 100 μmol/L) from nonfailing (donor hearts, n=13) and terminally failing (heart transplants, dilated cardiomyopathy, n=17) human myocardium were studied. In the same hearts, protein levels (Western blot analysis) and mRNA levels (Northern blot analysis) of SERCA II and phospholamban were measured. Increasing concentrations of Ca2+ were followed by an increased Ca2+-ATPase activity and Ca2+ uptake. Ca2+ uptake activity and Ca2+-ATPase activity in CSR preparations from failing myocardium were significantly reduced compared with nonfailing hearts (Ca2+-ATPase, 163±8 and 125±7 nmol ATP/mg protein per minu...
TL;DR: This discussion of “designing for comprehension” addresses the second type of task—reading a hyperdocument for learning—that is more adequate for tasks requiring deep understanding and learning.
Abstract: hypermedia, it is necessary to distinguish between two kinds of applications: “One encourages those who wish to wander through large clouds of information, gathering knowledge along the way. The other is more directly tied to specific problem-solving, and is quite structured and perhaps even constrained” [20, p. 119]. Applications of the first type appear as browsable databases—or hyperbases—that can be freely explored by a reader. In contrast, applications of the second type take the shape of electronic documents—or hyperdocuments—that intentionally guide readers through an information space, controlling their exploration along the lines of a predefined structure. Each type has its particular advantages and encourages different reading strategies. While the first one is better suited to support unconstrained search and information retrieval, the second one is more adequate for tasks requiring deep understanding and learning. As Hammond points out, it “may be fun and perhaps instructive, to open every door and peer inside, but there are many situations where learning is most effective when the freedom of the learner is restricted to a relevant and helpful subset of activities.” It is this second type of task—reading a hyperdocument for learning—that we address in our discussion of “designing for comprehension.”
TL;DR: In this paper, the authors identify receptors that transduce extracellular matrix signals into cellular events, resulting in reprogramming of connective tissue metabolism, and demonstrate that in human skin fibroblasts alpha 1 beta 1 and alpha 2 beta 1 integrins are the major receptors responsible for regulating ECM remodeling.
Abstract: The reorganization of extracellular matrix (ECM) is an important function in many biological and pathophysiological processes. Culture of fibroblasts in a three-dimensional collagenous environment represents a suitable system to study the underlying mechanisms resulting from cell-ECM interaction, which leads to reprogramming of fibroblast biosynthetic capacity. The aim of this study was to identify receptors that transduce ECM signals into cellular events, resulting in reprogramming of connective tissue metabolism. Our data demonstrate that in human skin fibroblasts alpha 1 beta 1 and alpha 2 beta 1 integrins are the major receptors responsible for regulating ECM remodeling: alpha 1 beta 1 mediates the signals inducing downregulation of collagen gene expression, whereas the alpha 2 beta 1 integrin mediates induction of collagenase (MMP-1). Applying mAb directed against different integrin subunits resulted in triggering the heterodimeric receptors and enhancing the normal biochemical response to receptor ligation. Different signal transduction inhibitors were tested for their influence on gel contraction, expression of alpha 1(I) collagen and MMP-1 in fibroblasts within collagen gels. Ortho-vanadate and herbimycin A displayed no significant effect on any of these three processes. In contrast, genistein reduced lattice contraction, and completely inhibited induction of MMP-1, whereas type I collagen down-regulation was unaltered. Calphostin C inhibited only lattice contraction. Taken together, these data indicate a role of tyrosine-specific protein kinases in mediating gel contraction and induction of MMP-1, as well as an involvement of protein kinase C in the contraction process. The data presented here indicate that different signaling pathways exist leading to the three events discussed here, and that these pathways do not per se depend upon each other.
TL;DR: Viable myocardium is characterized by preserved end-diastolic wall thickness and a dobutamine-inducible contraction reserve, and both parameters should be taken into account to maximize the sensitivity of MRI in the detection of regions with signs of viability on FDG-PET images.
Abstract: Background There have been conflicting reports of whether substantial myocardial thinning alone as an indirect sign of myocardial scarring is sufficient evidence to exclude the presence of viable m...
TL;DR: Analysis and sorting of hybridoma cells, according to secreted antibodies, and of activated T lymphocytes, accordingto secreted cytokines are described.
Abstract: We have developed a technology for analysis and sorting of live cells according to secreted molecules An artificial affinity matrix, specific for the secreted product of interest, is created on the cell surface, and the cells are allowed to secrete for a defined time period The secreted molecules bind to the affinity matrix on the secreting cell and are subsequently labeled with specific fluorescent or magnetic staining reagents for cytometric analysis and cell sorting Crossfeeding of the secreted products to other cells is prevented by decreasing the permeability of the incubation medium This approach will have a wide range of applications in biotechnology and biomedical research Here, we describe analysis and sorting of hybridoma cells, according to secreted antibodies, and of activated T lymphocytes, according to secreted cytokines
TL;DR: Doctors and surgeons should keep Hanley's simple formula in mind when complication rates of zero are reported in the literature and when they have not (yet) experienced a disastrous complication in a procedure.
Abstract: The probability of adverse and undesirable events during and after operations that have not yet occurred in a finite number of patients (n) can be estimated with Hanley's simple formula, which gives the upper limit of the 95% confidence interval of the probability of such an event: upper limit of 95% confidence interval=maximum risk=3/n (for n>30). Doctors and surgeons should keep this simple rule in mind when complication rates of zero are reported in the literature and when they have not (yet) experienced a disastrous complication in a procedure.
Just as aeroplanes should not crash, common bile ducts should not be cut and iliac vessels not be punctured during laparoscopic procedures. In reality, however, these things do happen.1 With the boom in endoscopic surgery, surgeons are claiming to have zero mortality or even zero morbidity in their series of operations. A little reminder, not only for surgeons, may be necessary. If a certain adverse event or complication does not occur in a series, it does not mean that it will never …
TL;DR: A phenomenological theory is developed that predicts the critical exponents for this transition and explains the self-organizing behavior of the outflow from a traffic jam and are consistent with all of the numerical results.
Abstract: We study a single-lane traffic model that is based on human driving behavior. The outflow from a traffic jam self-organizes to a critical state of maximum throughput. Small perturbations of the outflow far downstream create emergent traffic jams with a power law distribution P(t)\ensuremath{\sim}${\mathit{t}}^{\mathrm{\ensuremath{-}}3/2}$ of lifetimes t. On varying the vehicle density in a closed system, this critical state separates lamellar and jammed regimes and exhibits 1/f noise in the power spectrum. Using random walk arguments, in conjunction with a cascade equation, we develop a phenomenological theory that predicts the critical exponents for this transition and explains the self-organizing behavior. These predictions are consistent with all of our numerical results.
TL;DR: The number and timing of the primary and secondary endosymbiotic events that have resulted in the complex array of extant plastids are addressed and the findings are discussed in relation to existing ultrastructural, biochemical, and sequence data.
Abstract: Because photosynthesis has played such a fundamental role in shaping the biosphere, the origins of the plastids have remained one of the most intriguing and well-researched topics in biology. The initial formulation of the theory of endosymbiosis as an explanation for plastid origins (Schimper 1883, Mereschkowsky 1905.1910, Margulis 1981)hasbeen followed by a myriad of biochemical, ultrastructural, and molecular biological analyses of these organelles. These studies have provided many important clues that, together, begin to unravel the complex evolutionary history of plastids (for reviews see Martin et al. 1992, Lewin 1993, Palmer 1993, Douglas 1994, Loiseaux-de-Goer 1994). The vast existing body of literature on plastid endosymbiosis and evolution necessarily limits the quantity of data that may be successfully analyzed in a synopsis of this theme. We have, therefore, narrowed our focus considerably and addressed the evolutionary relationships and origin of plastids from the perspective of molecular evolutionary analyses of plastidand nuclear-encoded small-subunit ribosomal RNA (ssu rRNA) coding regions. Analysis of plastid and \"host\" cell phylogenies provides a powerful tool for testing the consistency of hypotheses regarding the evolutionary relationships of plastids by direct comparison to the relationships ofthe host cells that contain them. Using this simple test, we expect that when plastids share a monophyletic origin within a lineage (e.g. green algae, red algae), topologies inferred from the phylogenetic analyses of plastidand nuclear-encoded (i.e. host cell) ssu rRNAs will be approximately congruent (given that the seqtiences themselves do not contain extreme biases). From such comparisons, we wish to address the number and timing of the primary and secondary endosymbiotic events that have resulted in the complex array of extant plastids and discuss these findings in relation to existing ultrastructural, biochemical, and sequence data. The ssu rRNAs are
TL;DR: Using multivariate analysis, 3 independent predictors of mortality were identified: the presence of a rapidly or ultimately fatal underlying disease, septic shock at the onset of bacteremia, and mechanical ventilation.
TL;DR: Induction of the structurally conserved, spliced switch transcripts is sufficient to target switch recombination to IgG1, whereas transcription alone is not.
Abstract: B cells can exchange gene segments for the constant region of the immunoglobulin heavy chain, altering the class and effector function of the antibodies that they produce. Class switching is directed to distinct classes by cytokines, which induce transcription of the targeted DNA sequences. These transcripts are processed, resulting in spliced "switch" transcripts. Switch recombination can be directed to immunoglobulin G1 (IgG) by the heterologous human metallothionein IIA promoter in mutant mice. Induction of the structurally conserved, spliced switch transcripts is sufficient to target switch recombination to IgG1, whereas transcription alone is not.
TL;DR: In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity, which can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only.
TL;DR: Data provide circumstantial evidence that singlet oxygen mediates the UVA induction of collagenase in vitro, whereas it does not exert any effect on TIMP-1 synthesis.
TL;DR: The Niemann-Pick mouse might facilitate studies on the function of aSMase in the generation of ceramide as proposed second messenger in the intracellular signaling pathways and across the plasma membrane, and provides a suitable model for the development of strategies for somatic gene therapy.
TL;DR: It is shown that the induction of vg, which initiates wing development in Drosophila, requires the combined activities of Ser, wg and Notch, and it is proposed that Ser is a dorsal signal and Wg is a ventral signal, and that their combination at the dorso-ventral interface activates the Notch receptor and leads to vg expression.
TL;DR: Actin dynamics were similar in lcsA‐ and ActA‐induced actin tails suggesting that by using unrelated surface molecules, L. monocytogenes and S. flexneri move intracellularly by interacting with the same host cytoskeleton components or by interfering with theSame host cell signal transduction pathway.
Abstract: Listeria monocytogenes and Shigella flexneri are two unrelated facultative intracellular pathogens which spread from cell to cell by using a similar mode of intracellular movement based on continuous actin assembly at one pole of the bacterium. This process requires the asymmetrical expression of the ActA surface protein in L. monocytogenes and the lcsA (VirG) surface protein in S. flexneri. ActA and lcsA share no sequence homology. To assess the role of the two proteins in the generation of actin-based movement, we expressed them in the genetic context of two non-actin polymerizing, non-pathogenic bacterial species, Listeria innocua and Escherichia coli. In the absence of any additional bacterial pathogenicity determinants, both proteins induced actin assembly and propulsion of the bacteria in cytoplasmic extracts from Xenopus eggs, as visualized by the formation of characteristic actin comet tails. E. coli expressing lcsA moved about two times faster than Listeria and displayed longer actin tails. However, actin dynamics (actin filament distribution and filament half-lives) were similar in lcsA- and ActA-induced actin tails suggesting that by using unrelated surface molecules, L. monocytogenes and S. flexneri move intracellularly by interacting with the same host cytoskeleton components or by interfering with the same host cell signal transduction pathway.
TL;DR: It is believed that postoperative radiation therapy alone cannot be advocated as a adjuvant therapy following curative resection of squamous cell carcinoma of the esophagus.
Abstract: Postoperative radiation therapy following curative resection of squamous cell carcinoma of the esophagus was investigated in a prospective randomized study. A group of 33 patients received postoperative radiation therapy and were compared to a control group of 35 patients treated by surgery alone. No statistically significant differences were noted between the two treatment groups concerning overall and disease-free survival rates. Postoperative irradiation significantly increased the incidence of fibrotic strictures of the esophagogastric or esophagocolonic anastomoses and caused a delayed recovery of patients quality of life. Based on these results, we believe that postoperative radiation therapy alone cannot be advocated as a adjuvant therapy following curative resection of squamous cell carcinoma of the esophagus.
TL;DR: In the roots of pea plants (Pisum sativum L.) cultivated with 20 [mu]M CdCl2 for 3 d, synthesis of phytochelatins [PCs or ([gamma]EC)nG] is accompanied by a drastic decrease in glutathione content, but an increase in homoglutathione (h-GSH) content.
Abstract: In the roots of pea plants (Pisum sativum L.) cultivated with 20 [mu]M CdCl2 for 3 d, synthesis of phytochelatins [PCs or ([gamma]EC)nG, where [gamma]EC is [gamma]glutamylcysteine and G is glycine] and homophytochelatins [h-PCs, ([gamma]EC)n[beta]-alanine] is accompanied by a drastic decrease in glutathione (GSH) content, but an increase in homoglutathione (h-GSH) content. In contrast, the in vitro activity of GSH synthetase increases 5-fold, whereas h-GSH synthetase activity increases regardless of Cd exposure. The consititutive enzyme PC synthase, which catalyzes the transfer of the [gamma]-EC moiety of GSH to an acceptor GSH molecule thus producing ([gamma]EC)2G, is activated by heavy metals, with Cd and Cu being strong activators and Zn being a very poor activator. Using h-GSH or hm-GSH for substrate, the synthesis rate of([gamma]EC)2[beta]-alanine and [gamma]EC)2-serine is only 2.4 and 0.3%, respectively, of the sythesis rate of ([gamma]EC)2G with GSH as substrate. However, in the presence of a constant GSH level, increasing the concentration of h-GSH or hm-GSH results in increased synthesis of ([gamma]EC)2[beta]-alanine or ([gamma]EC)2-serine, respecively; simultaneously, the synthesis of ([gamma]EC)2G is inhibited. [gamma]EC is not a substrate of PC synthase. These results are best explained by assuming that PC synthase has a [gamma]EC donor binding site, which is very specific for GSH, and a [gamma]EC acceptor binding site, which is less specific and accepts several tripeptides, namely GSH, h-GSH, and hm-GSH.