Visualization of tumor growth and response to NK-T cell based immunotherapy using bioluminescence.
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Animals↗
Biomedical subjects
M Bachmann
Publications and source records attributed to M Bachmann.
Fluctuation pressure of a stack of membranes.
We calculate the universal constants in Helfrich's pressure law for a stack of N membranes between walls by strong-coupling theory. Using the close analogy between this system and a stack of strings, where the universal constants are exactly known, we construct a smooth potential that keeps the membranes apart. The strong-coupling limit of the perturbative treatment of the free energy yields pressure constants for an arbitrary number of membranes, which are in very good agreement with values from Monte Carlo simulations.
Journal Article↗
The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3.
STAT factors act as signal transducers of cytokine receptors and transcriptionally activate specific target genes. The recently discovered protein PIAS3 binds directly to STAT3 and blocks transcriptional activation. Here, we present experimental evidence implementing the zinc finger protein Gfi-1 as a new regulatory factor in STAT3-mediated signal transduction. The interaction between the two proteins first became evident in a yeast two-hybrid screen but was also seen in coprecipitation experiments from eukaryotic cells. Moreover, we found that both Gfi-1 and PIAS3 colocalize in a characteristic nuclear dot structure. While PIAS3 exerts a profound inhibitory effect on STAT3-mediated transcription of target promoters, Gfi-1 can overcome the PIAS3 block and significantly enhances STAT3-mediated transcriptional activation. In primary T cells, Gfi-1 was able to amplify IL-6-dependent T-cell activation. As Gfi-1 is a known, dominant proto-oncogene, our findings bear particular importance for the recently described ability of STAT3 to transform cells malignantly and offer an explanation of the oncogenic potential of Gfi-1 in T lymphocytes.
Animals↗
Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes.
Dendritic cells (DCs) exhibit considerable heterogeneity in their anatomical location, surface phenotype, and functional properties. In this study, we demonstrate that peripheral lymph nodes contain at least four major, functionally separable, and independently derived, DC subsets, which can be clearly demarcated by their CD11c, CD40, and CD8 expression pattern. Surprisingly, all DCs derived directly from the bone marrow, the myeloid- and the lymphoid-related subsets, turned over fast with t(1/2) of a couple of days. In contrast, DCs exported from the skin, both dermal and epidermal, accumulated 3- to 4-fold slower, turnover that is dramatically increased by cutaneous inflammation.
Administration, Cutaneous↗
Transcription efficiency of human polymerase III genes in vitro does not depend on the RNP-forming autoantigen La.
Transcription of class III genes is conducted by multi-protein complexes consisting of polymerase III itself and several transcription factors. We established a reconstituted in vitro transcription system from which the autoantigen La was removed by immunodepletion. This system showed no RNP formation, but was still fully active in transcription. Supplementing such La-free transcription reactions with recombinant La restored the formation of La complexes with the newly synthesised RNA, but did not lead to enhanced transcription efficiency. Furthermore, we developed a technique for the generation and isolation of transcription complexes, assembled from purified transcription factors and isolated by glycerol centrifugation. These complexes were fully competent to re-initiate RNA synthesis but they were not associated with La and their transcription rate could not be stimulated by addition of recombinant La. Therefore, we conclude that La does not act as a human polymerase III transcription factor.
Antibodies↗
In vitro analysis of verapamil-induced immunosuppression: potent inhibition of T cell motility and lymphocytic transmigration through allogeneic endothelial cells.
BACKGROUND: Cyclosporine A (CsA) and tacrolimus prevent proliferation but not transendothelial migration of alloreactive lymphocytes into donor organs. As a result, serious adverse effects, such as nephrotoxicity and neurotoxicity, have been observed under CsA/tacrolimus therapy. The incorporation of new drugs with infiltration blocking properties might enhance the efficacy of the current immunosuppressive protocol, allowing lower CsA/tacrolimus dosage. Because Ca2+ plays a critical role in cell-cell interaction, the Ca2+-channel blocker verapamil might be a good cany. didate for supporting CsA/tacrolimus-based therapy. METHODS: A T-cell endothelial cell coculture model or immobilized immunoglobulin G globulin chimeras were employed to investigate how S- and R- verapamil interfere with the lymphocytic infiltration process. The expression and arrangement of membranous adhesion receptors and cytoskeletal F-actin filaments were analyzed by fluorometric method in the presence of. verapamil. RESULTS: Both verapamil enantiomers strongly inhibited lymphocyte infiltration. CD4+ and CD8+ T-cells were influenced to a similar extent with regard to horizontal locomotion (CD4+=CD8+), but to a different extent with regard to adhesion and penetration (CD4+ > CD8+). Moreover, penetration was blocked to a higher extent than was adhesion. ID50-values were 31 microM (CD4+-adhesion) and 11 microM (CD4+-penetration). Verapamil reduced P-selectin expression on endothelial cells and effectively down-regulated binding of T-cells to immobilized P-selectin immunoglobulin G globulins (ID50=4.4 microM; CD4+). A verapamil-induced reduction of intracellular F-actin in T-lymphocytes was proven to be mainly responsible for diminished cell locomotion. CONCLUSIONS: The prevention of CD4+ T-cell penetration by verapamil might argue for its use as an adjunct to CsA/tacrolimus-based immunosuppressive therapy.
Cell Movement↗
High frequency of t(14;18) translocation in Sjögren's syndrome: comment on the article by Gellrich et al.
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Chromosomes, Human, Pair 14↗
[Trichobezoar in a 16-year old girl. Case report and review of literature].
We present the case of a 16-year-old girl with a 12-year history of trichotillomania and trichotillophagia in combination with mental retardation and early childhood deprivation, all contributing to the growth of a stomach ulcer and an oversized, stomach-shaped trichobezoar which had to be removed by gastrotomy. Included are a discussion of psychodynamic aspects, therapeutic strategies, and significant literature, concluding with a short, historic view on the varieties and therapy of bezoars.
Adolescent↗
Frequency and evaluation of t(14;18) translocation in Sjögren's syndrome.
In most cases of follicular lymphoma, t(14;18) chromosomal translocation can be detected in lymphocytes of peripheral blood and bone marrow. Nevertheless, certain other types of diseases can also be characterised by the presence of the translocation. Patients of Sjogren's syndrome have an increased frequency of developing non-Hodgkin's lymphoma, e.g. follicular lymphoma; in turn, they may have translocation-bearing cells. One hundred Sjögren's syndrome patients were screened using a nested polymerase chain reaction technique to identify whether they had the translocation in their peripheral blood lymphocytes. Five percent of that population revealed a temporary or long-lasting presence of the translocation, sometimes even in the lymphocytes from bone marrow. Our results indicate that in addition to the conventional diagnostic methods of lymphoma, there are certain other factors, e.g. the duration of the presence of t(14; 18) translocation and the source of lymphocytes, that should be considered for successful early diagnoses and perhaps for treatment of the lymphoma in the Sjögren's patients.
Base Sequence↗
Developmentally regulated TCR efficiency
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Journal Article↗
The effect of skin diseases on quality of life in patients from different social and ethnic groups in Cape Town, South Africa.
BACKGROUND: Skin diseases can greatly affect the quality of life (QoL). Little is known, however, of their impact on QoL in the developing world. This study was designed to assess the effect of skin diseases in such a setting. METHODS: A questionnaire survey of patients using the Dermatology Life Quality Index (DLQI), modified to the cultural needs of the population. The adapted instrument was translated into Afrikaans and Xhosa. Six hundred and seven patients attending general dermatology clinics at Groote Schuur Hospital and 53 controls were recruited. Influences on QoL of clinical severity, employment, education, age, sex, and home language were examined. RESULTS: Participants included 313 (52%) English-speaking, 215 (35%) Afrikaans-speaking, and 79 (13%) Xhosa-speaking dermatology patients. Independent risk factors for having a high disability score were dermatologists' assessment of severity, younger age, unemployment, and language (odds ratio, 0.13; 95% confidence interval (CI) of 0. 03-0.5 for Xhosa speakers compared to Afrikaans speakers). Gender was not associated with a high score, but females were more likely to report effects of skin disease on self-esteem, clothing choice, treatment problems, and anxiety. CONCLUSIONS: In this multicultural setting, social class and language group, but not gender, influenced the impact of skin disease on overall QoL. Xhosa speakers were apparently less affected than other patients. This could be due to cultural differences in the experience of skin disease and in the perception of disability, or to biases in questionnaire responses. Anxiety and depression were relevant dimensions of QoL in this study and should be considered for inclusion in future research. The adapted and translated DLQI was valid and reliable.
Adult↗
LaXp180, a mammalian ActA-binding protein, identified with the yeast two-hybrid system, co-localizes with intracellular Listeria monocytogenes.
The Listeria monocytogenes surface protein ActA is an important virulence factor required for listerial intracellular movement by inducing actin polymerization. The only host cell protein known that directly interacts with ActA is the phosphoprotein VASP, which binds to the central proline-rich repeat region of ActA. To identify additional ActA-binding proteins, we applied the yeast two-hybrid system to search for mouse proteins that interact with ActA. A mouse cDNA library was screened for ActA-interacting proteins (AIPs) using ActA from strain L. monocytogenes EGD as bait. Three different AIPs were identified, one of which was identical to the human protein LaXp180 (also called CC1). Binding of LaXp180 to ActA was also demonstrated in vitro using recombinant histidine-tagged LaXp180 and recombinant ActA. Using an anti-LaXp180 antibody and fluorescence microscopy, we showed that LaXp180 co-localizes with a subset of intracellular, ActA-expressing L. monocytogenes but was never detected on intracellularly growing but ActA-deficient mutants. Furthermore, LaXp180 binding to intracellular L. monocytogenes was asymmetrical and mutually exclusive with F-actin polymerization on the bacterial surface. LaXp180 is a putative binding partner of stathmin, a protein involved in signal transduction pathways and in the regulation of microtubule dynamics. Using immunofluorescence, we showed that stathmin co-localizes with intracellular ActA-expressing L. monocytogenes.
Actins↗
Medical or surgical treatment for chronic gastrooesophageal reflux? A systematic review of published evidence of effectiveness.
OBJECTIVE: To compare the effectiveness of medical (antacids, histamine antagonists and proton pump inhibitors) and surgical (fundoplication) treatment of chronic GORD. SUBJECTS: Patients with objective (endoscopic or pH) evidence of chronic reflux reported in 6 randomised trials and 3 cohort studies, 1966-1999. METHODS: Systematic review of comparative studies identified from electronic searches, citations, manual searches of journals, and correspondence with authors and experts. MAIN OUTCOME MEASURES: Improvements in prevalence or severity of symptoms, oesophagitis, pH reflux duration, lower oesophageal sphincter pressure, patients' satisfaction, and side-effects. RESULTS: Improved outcomes were more common after surgical than medical treatment with significant differences in objective outcomes in 5/6 randomised trials and in 2/3 cohort studies. Subjective outcomes (symptoms and patients' satisfaction) were also more common among surgical patients in all but one study that assessed them. Odds ratios for improvement with surgical rather than medical treatment ranged from 1.2 to 200, and numbers needed to treat ranged from 1.2 to 58, where these could be calculated. Studies were too heterogeneous for meta-analysis. CONCLUSIONS: In trials of chronic severe GORD, surgery is consistently more effective than medical treatment in relieving symptoms and objective oesophagitis, although omeprazole can give similar symptom relief with adjustment of the dose.
Adult↗
Recursive graphical construction of feynman diagrams and their multiplicities in straight phi(4) and straight phi2A theory
The free energy of a field theory can be considered as a functional of the free correlation function. As such it obeys a nonlinear functional differential equation that can be turned into a recursion relation. This is solved order by order in the coupling constant to find all connected vacuum diagrams with their proper multiplicities. The procedure is applied to a multicomponent scalar field theory with a straight phi(4) self-interaction and then to a theory of two scalar fields straight phi and A with an interaction straight phi2A. All Feynman diagrams with external lines are obtained from functional derivatives of the connected vacuum diagrams with respect to the free correlation function. Finally, the recursive graphical construction is automatized by computer algebra with the help of a unique matrix notation for the Feynman diagrams.
Journal Article↗
Generation of an apoptotic intracellular peptide by gamma-secretase cleavage of Alzheimer's amyloid beta protein precursor.
The amyloid beta protein precursor (AbetaPP) is sequentially processed by beta- and gamma-secretases to generate the Abeta peptide. The biochemical path leading to Abeta formation has been extensively studied since extracellular aggregates of amyloidogenic forms of Abeta peptide (Abeta42) are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of AbetaPP proteolysis is unknown. Although never previously described, cleavage of AbetaPP by gamma-secretase should release, together with Abeta, a COOH-terminal AbetaPP Intracellular Domain, herein termed AID. We have now identified AID-like peptides in brain tissue of normal control and patients with sporadic Alzheimer's disease and demonstrate that AID acts as a positive regulator of apoptosis. Thus, overproduction of AID may add to the toxic effect of Abeta42 aggregates and further accelerate neurodegeneration.
Journal Article↗
Overexpression and functional characterization of kinin receptors reveal subtype-specific phosphorylation.
G protein-coupled receptors such as the receptors for bradykinin are present in low copy numbers in most natural cells. To overcome the problems associated with the analysis of these receptors at the protein level, we used highly efficient expression systems such as the baculovirus/insect cell system. However, the structural and functional statuses of recombinant receptors have often remained elusive. We have expressed the two types of human kinin receptors, B1 and B2, in Sf9 cells. Both receptors are found on the surface of infected cells where they display the same pharmacological profiles as their cognate receptors of native cells. The functional analysis of kinin receptors coupled to the intracellular signaling pathways of Sf9 cells revealed differential patterns of ligand-induced phosphorylation for the two kinin receptors. The B1 receptor failed to undergo ligand-induced phosphorylation. However the B2 receptor showed selective phosphorylation of a minor 38 kDa band and lack of phosphorylation of a dominant 33 kDa band, indicating that only a fraction of the receptor protein is functionally linked to the kinase pathway. A striking discrepancy between the number of binding sites and the amount of receptor protein per cell (molar ratio of 1:20 to 1:1000) indicated that a significant portion of kinin receptors is associated with the intracellular compartments of Sf9 cells. Pulse-chase and immunoprecipitation experiments demonstrated that the heterogeneity of recombinant receptors is not due to proteolytic processing but likely reflects incomplete or lacking N-glycosylation. We conclude that the baculovirus/Sf9 system is suitable for the recombinant expression and functional analysis of kinin receptors though limitations of the system have to be considered.
Animals↗
Stimulation with carbachol alters endomembrane distribution and plasma membrane expression of intracellular proteins in lacrimal acinar cells.
The events that lead to Sjögren's autoimmune processes in the lacrimal gland remain poorly understood. The acinar cell's responses to acute cholinergic stimulation include release of secretory products across the apical plasma membrane (apm) and a number of processes related to traffic between endomembrane compartments and the basal-lateral plasma membranes (blm), such as recruitment of Na, K-ATPase, accelerated recycling, and accelerated transcytosis of secretory IgA. We tested the hypothesis that stimulation-induced acceleration of endomembrane traffic is accompanied by changes in compartmentation and increased blm expression of proteins that are normally sequestered in endomembrane compartments. Isolated rabbit lacrimal gland acinar cells were cultured in serum-free media for 2 days. After harvesting, cells were incubated with or without 10 microm carbachol at 37 degrees C for 20 min. Cells were lysed, and lysates were analysed by isopycnic centrifugation on sorbitol gradients. Galactosyltransferase catalytic activity was determined biochemically. Different forms of cathepsin B were detected by Western blotting. Carbachol stimulation decreased the contents of beta-hexosaminidase, alpha-glucosidase, and protein in secretory vesicles and increased them in specific compartments of the trans-Golgi network (ld-tgns). Stimulation also caused levels of galactosyltransferase, preprocathepsin B, and procathepsin B to increase two- to three-fold in the blm as well as increasing in the ld-tgns. Other changes caused by sustained stimulation included: (a) increased levels of protein and procathepsin B in compartments of the lysosomal pathway; (b) changes in the distributions of Rab5 within the endomembrane system; (c) changes in the distribution of Rab6 within the Golgi complex and tgn; (d) decreased expression of acid phosphatase and MHC class II molecules in the blm; and (e) decreased total content of Na,K-ATPase, which appeared to have been selectively depleted from the tgn and blmre. We propose that the normal compartmentation of certain proteins may allow them to remain cryptic, such that they are not subject to central tolerance. Stimulation-induced increases in the levels expressed at the blm or secreted to the interstitium may, therefore, contribute to initiation of local autoimmune responses.
Acid Phosphatase↗
Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses.
Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and nonallergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threatening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)-4-deficient (IL-4-/-) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-4-/- mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was associated with decreased lung inflammatory pathology, impaired T helper (Th)-2 responses (including lung eosinophilia), and an IL-12-dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-12-/- and interferon-gamma-/- mice and in IL-4-/- mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 responses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungus.
Animals↗