Rectal carcinoma unmasked by mud packs.
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Adenocarcinoma↗
Biomedical subjects
T Weber
Publications and source records attributed to T Weber.
Evidence that an additional mutation is required to tolerate insertional inactivation of the Streptomyces lividans recA gene.
In contrast to recA of other bacteria, the recA gene of Streptomyces lividans has been described as indispensable for viability (G. Muth, D. Frese, A. Kleber, and W. Wohlleben, Mol. Gen. Genet. 255:420-428, 1997.). Therefore, a closer analysis of this gene was performed to detect possible unique features distinguishing the Streptomyces RecA protein from the well-characterized Escherichia coli RecA protein. The S. lividans recA gene restored UV resistance and recombination activity of an E. coli recA mutant. Also, transcriptional regulation was similar to that of E. coli recA. Gel retardation experiments showed that S. lividans recA is also under control of the Streptomyces SOS repressor LexA. The S. lividans recA gene could be replaced only by simultaneously expressing a plasmid encoded recA copy. Surprisingly, the recA expression plasmid could subsequently be eliminated using an incompatible plasmid without the loss of viability. Besides being UV sensitive and recombination deficient, all the mutants were blocked in sporulation. Genetic complementation restored UV resistance and recombination activity but did not affect the sporulation defect. This indicated that all the recA mutants had suffered from an additional mutation, which might allow toleration of a recA deficiency.
Bacterial Proteins↗
Images in cardiology: Kawasaki's disease.
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Adult↗
Vitamin E analogues as inducers of apoptosis: implications for their potential antineoplastic role.
Recent evidence suggests that vitamin E and its analogues, which have been used for many years as antioxidants, may not only protect cells from free radical damage but also induce apoptotic cell death in various cell types. While alpha-tocopherol (alpha-TOH) is mainly known as an anti-apoptotic agent, its redox-silent analogues either have no influence on cell survival (alpha-tocopheryl acetate, alpha-TOA), or induce apoptosis (alpha-tocopheryl succinate, alpha-TOS). Although precise mechanisms of apoptosis induction by alpha-TOS remain to be elucidated, there is evidence that this process involves both the antiproliferative and membrane destabilising activities of the agent. Alpha-TOS has been shown to induce apoptosis in malignant cell lines but not, in general, in normal cells, and to inhibit tumorigenesis in vivo. These features suggest that this semi-synthetic analogue of vitamin E could be a promising antineoplastic agent.
Adenocarcinoma↗
[Pharmacologic interventions in primary prevention: lipid lowering drugs, aspirin, antiobesity drugs, and antihypertensive agents].
Heart disease, particularly coronary heart disease is a major cause of morbidity and mortality in developed countries. Cardiovascular disease accounts for more than 50% of deaths. Drug therapy is highly effective for treatment of patients after a first cardiovascular event (secondary prevention). In contrast, introduction of drug therapy for lowering cardiovascular risk before a first cardiovascular event (primary prevention) is discussed controversially. The number of persons who need to be treated for prevention of one cardiovascular event is high and drug therapy in more or less "healthy" people is justified only after accurate assessment of potential risks and possible beneficial effects. Drug therapy combined with non-pharmacological treatment strategies is considered to be appropriate in selected high-risk persons for primary prevention. The following article describes potential indications of several drugs, in particular cholesterol-lowering therapy, aspirin, drug therapy of obesity and hypertension, for use in primary prevention of cardiovascular disease.
Anti-Obesity Agents↗
[Homocysteine and cardiovascular risk].
Homocysteine is an amino acid that plays a key role in methionine- and homocysteine metabolism. Homocystinuria has been described about four decades ago to be an inherited (autosomal recessive) disorder with rapid progressive atherosclerosis. Thus, homocysteine has been investigated intensively with respect to vascular wall injury and atherogenesis. Folic acid and vitamin B12 are cofactors of methioninsynthase, a key enzyme in homocysteine metabolism. Plasma levels of homocysteine are higher in patients with coronary artery disease documented by coronary angiography than in individuals with normal coronary arteries. Supplementation of folic acid is the treatment of choice to lower plasma homocysteine concentrations. Improvement in endothelial function could be documented in patients with folic acid supplementation. Large scaled clinical trials investigating folic acid supplementation in secondary prevention are now in progress. Today, homocysteine and its association with atherosclerosis raise a lot of questions to be answered. A distinct pathophysiological model linking hyperhomocysteinaemia and atherosclerosis is still not available. The presence of hyperhomocysteinemia in atherosclerotic vascular disease as a surrogate with no pathophysiological relevance itself cannot be ruled out. Routine testing of homocysteine levels is not yet recommended. Treatment of patients with folic acid or vitamin B for primary and secondary prevention of atherosclerotic vascular disease cannot be recommended today, because large scaled intervention trials on homocysteine lowering by vitamin B or folic acid are not available yet. Possible effects of these interventions on acute vascular events are not known.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Cellular and humoral immune response in progressive multifocal leukoencephalopathy.
Progressive multifocal leukoencephalopathy (PML) is a fatal, demyelinating disease caused by JC virus (JCV) in patients with severe immunosuppression. We studied the JCV-specific cellular and humoral immune response in 7 healthy donors (HD), 6 human immunodeficiency virus-1 (HIV-1)-infected patients without PML (HIV), 4 HIV-1-negative patients with PML (PML), and 8 HIV-1-positive patients with PML (HIV/PML). As antigens, recombinant virus-like particles of the major structural protein VP1 (VP1-VLP) of JCV, tetanus toxoid (TT), or the mitogen phytohemagglutinin (PHA) were used. Proliferation of peripheral blood mononuclear cells (PBMC) after stimulation with the VP1-VLP was significantly suppressed in PML and HIV/PML patients compared to HD. After antigen stimulation the production of interferon-gamma (IFN-gamma) was reduced in PML, in HIV/PML, and in HIV patients. The production of interleukin-10 (IL-10), however, was elevated in HIV/PML patients. Neither proliferation nor cytokine production correlated with the presence of JCV DNA in PBMC. The immunoglobulin G serum antibody titer to the VP1-VLP was slightly elevated in HIV, elevated in PML, and highly elevated in HIV/PML patients compared to HD. The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity.
Cytokines↗
[Morphine--myths and facts].
Morphine in the form of opium tincture accompanies the mankind for several thousands years. At the beginning of the twentieth century morphine has been isolated from opium and it was used initially to treat ... opium addicts. At present it plays an important role in the treatment of severe pain of different origins and (more seldom) in the premedication for general anaesthesia. Despite its side effects it is irreplaceable especially in the treatment of cancer pain. Nowadays the chronic use of oral morphine preparations has been supported by medical authorities who at the same time warn against incorrect dosage and combination with other drugs. Many clinical data concerning oral morphine show that it is safe and effective even in the patients with advanced cancer and poor performance status. Our paper lists myths and common mistakes connected with morphine use and confronts them with well established facts confirming its effectiveness in cancer pain treatment.
Administration, Oral↗
NMR structure of the N-SH2 of the p85 subunit of phosphoinositide 3-kinase complexed to a doubly phosphorylated peptide reveals a second phosphotyrosine binding site.
The N-terminal src homology 2 (SH2) domain of the p85 subunit of phosphoinositide 3-kinase (PI3K) has a higher affinity for a peptide with two phosphotyrosines than for the same peptide with only one. This unexpected result was not observed for the C-terminal SH2 from the same protein. NMR structural analysis has been used to understand the behavior of the N-SH2. The structure of the free SH2 domain has been compared to that of the SH2 complexed with a doubly phosphorylated peptide derived from polyomavirus middle T antigen (MT). The structure of the free SH2 domain shows some differences from previous NMR and X-ray structures. In the N-SH2 complexed with a doubly phosphorylated peptide, a second site for phosphotyrosine interaction has been identified. Further, line shapes of NMR signals showed that the SH2 protein-ligand complex is subject to temperature-dependent conformational mobility. Conformational mobility is also supported by the spectra of the ligand peptide. A binding model which accounts for these results is developed.
Amino Acid Sequence↗
Functional architecture of an intracellular membrane t-SNARE.
Lipid bilayer fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, of which one is supplied by the v-SNARE and the other three by the t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and a SNAP-25 protein contributes the other two. Although there are numerous homologues of syntaxin on intracellular membranes, there are only two SNAP-25-related proteins in yeast, Sec9 and Spo20, both of which are localized to the plasma membrane and function in secretion and sporulation, respectively. What replaces SNAP-25 in t-SNAREs of intracellular membranes? Here we show that an intracellular t-SNARE is built from a 'heavy chain' homologous to syntaxin and two separate non-syntaxin 'light chains'. SNAP-25 may thus be the exception rather than the rule, having been derived from genes that encoded separate light chains that fused during evolution to produce a single gene encoding one protein with two helices.
Escherichia coli↗
Molecular characterization of the transition state regulator AbrB from Bacillus stearothermophilus.
The Bacillus subtilis transition state regulator AbrB(su) is a DNA-binding protein that acts on several genes either as activator, repressor, or preventer. However, among genes under its control, neither common binding sites could be identified nor could the structural features of this broad and specific interaction be elucidated. Attempts to elucidate these interesting features by crystallizing AbrB(su) have failed so far. Therefore, to solve this problem, we focused in this work on identifying an AbrB(su) homologue from Bacillus stearothermophilus. Using a novel method, the entire abrB(st) gene of B. stearothermophilus was cloned and sequenced. The gene encodes a 95 amino acid protein that shows 77% identity and 85% similarity to the mesophilic B. subtilis protein. A calmodulin binding peptide-tagged fusion of the thermophilic gene was constructed for overexpression and efficient affinity column purification of the AbrB(st) protein. The purified protein showed, after removal of the tag, an oligomerization behavior through hexamer formation that is essential for its DNA binding activity.
Amino Acid Sequence↗
Close is not enough: SNARE-dependent membrane fusion requires an active mechanism that transduces force to membrane anchors.
Is membrane fusion an essentially passive or an active process? It could be that fusion proteins simply need to pin two bilayers together long enough, and the bilayers could do the rest spontaneously. Or, it could be that the fusion proteins play an active role after pinning two bilayers, exerting force in the bilayer in one or another way to direct the fusion process. To distinguish these alternatives, we replaced one or both of the peptidic membrane anchors of exocytic vesicle (v)- and target membrane (t)-SNAREs (soluble N-ethylmaleimide-sensitive fusion protein [NSF] attachment protein [SNAP] receptor) with covalently attached lipids. Replacing either anchor with a phospholipid prevented fusion of liposomes by the isolated SNAREs, but still allowed assembly of trans-SNARE complexes docking vesicles. This result implies an active mechanism; if fusion occurred passively, simply holding the bilayers together long enough would have been sufficient. Studies using polyisoprenoid anchors ranging from 15-55 carbons and multiple phospholipid-containing anchors reveal distinct requirements for anchors of v- and t-SNAREs to function: v-SNAREs require anchors capable of spanning both leaflets, whereas t-SNAREs do not, so long as the anchor is sufficiently hydrophobic. These data, together with previous results showing fusion is inhibited as the length of the linker connecting the helical bundle-containing rod of the SNARE complex to the anchors is increased (McNew, J.A., T. Weber, D.M. Engelman, T.H. Sollner, and J.E. Rothman, 1999. Mol. Cell. 4:415-421), suggests a model in which one activity of the SNARE complex promoting fusion is to exert force on the anchors by pulling on the linkers. This motion would lead to the simultaneous inward movement of lipids from both bilayers, and in the case of the v-SNARE, from both leaflets.
Antigens, Surface↗
Correlated electron emission in multiphoton double ionization
Electronic correlations govern the dynamics of many phenomena in nature, such as chemical reactions and solid state effects, including superconductivity. Such correlation effects can be most clearly investigated in processes involving single atoms. In particular, the emission of two electrons from an atom--induced by the impact of a single photon, a charged particle or by a short laser pulse--has become the standard process for studies of dynamical electron correlations. Atoms and molecules exposed to laser fields that are comparable in intensity to the nuclear fields have extremely high probabilities for double ionization; this has been attributed to electron-electron interaction. Here we report a strong correlation between the magnitude and the direction of the momentum of two electrons that are emitted from an argon atom, driven by a femtosecond laser pulse (at 38 TW cm(-2)). Increasing the laser intensity causes the momentum correlation between the electrons to be lost, implying that a transition in the laser-atom coupling mechanism takes place.
Journal Article↗
SNAREpins are functionally resistant to disruption by NSF and alphaSNAP.
SNARE (SNAP [soluble NSF (N-ethylmaleimide-sensitive fusion protein) attachment protein] receptor) proteins are required for many fusion processes, and recent studies of isolated SNARE proteins reveal that they are inherently capable of fusing lipid bilayers. Cis-SNARE complexes (formed when vesicle SNAREs [v-SNAREs] and target membrane SNAREs [t-SNAREs] combine in the same membrane) are disrupted by the action of the abundant cytoplasmic ATPase NSF, which is necessary to maintain a supply of uncombined v- and t-SNAREs for fusion in cells. Fusion is mediated by these same SNARE proteins, forming trans-SNARE complexes between membranes. This raises an important question: why doesn't NSF disrupt these SNARE complexes as well, preventing fusion from occurring at all? Here, we report several lines of evidence that demonstrate that SNAREpins (trans-SNARE complexes) are in fact functionally resistant to NSF, and they become so at the moment they form and commit to fusion. This elegant design allows fusion to proceed locally in the face of an overall environment that massively favors SNARE disruption.
Adenosine Triphosphate↗
[New enemy for our hearts. What do we know today about the role of Chlamydia?].
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Chlamydia Infections↗
Solution structure of PCP, a prototype for the peptidyl carrier domains of modular peptide synthetases.
BACKGROUND: Nonribosomal peptide synthetases (NRPSs) are large modular enzymes responsible for the synthesis of a variety of microbial bioactive peptides. They consist of modules that each recognise and incorporate one specific amino acid into the peptide product. A module comprises several domains, which carry out the individual reaction steps. After activation by the adenylation domain, the amino acid substrate is covalently tethered to a 4'-phosphopantetheinyl cofactor of a peptidyl carrier domain (PCP) that passes the substrate to the reaction centres of the consecutive domains. RESULTS: The solution structure of PCP, a distinct peptidyl carrier protein derived from the equivalent domain of an NRPS, was solved using NMR techniques. PCP is a distorted four-helix bundle with an extended loop between the first two helices. Its overall fold resembles the topology of acyl carrier proteins (ACPs) from Escherichia coli fatty acid synthase and actinorhodin polyketide synthase from Streptomyces coelicolor; however, the surface polarity and the length and relative alignment of the helices are different. The conserved serine, which is the cofactor-binding site, has the same location as in the ACPs and is situated within a stretch of seven flexible residues. CONCLUSIONS: The structure of PCP reflects its character as a protein domain. The fold is well defined between residues 8 and 82 and the structural core of the PCP domain can now be defined as a region spanning 37 amino acids in both directions from the conserved serine. The flexibility of the post-translationally modified site might have implications for interactions with the cooperating proteins or NRPS domains.
Amino Acid Sequence↗
Putative fusogenic activity of NSF is restricted to a lipid mixture whose coalescence is also triggered by other factors.
It has recently been reported that N-ethylmaleimide-sensitive fusion ATPase (NSF) can fuse protein-free liposomes containing substantial amounts of 1,2-dioleoylphosphatidylserine (DOPS) and 1, 2-dioleoyl-phosphatidyl-ethanolamine (DOPE) (Otter-Nilsson et al., 1999). The authors impart physiological significance to this observation and propose to re-conceptualize the general role of NSF in fusion processes. We can confirm that isolated NSF can fuse liposomes of the specified composition. However, this activity of NSF is resistant to inactivation by N-ethylmaleimide and does not depend on the presence of alpha-SNAP (soluble NSF-attachment protein). Moreover, under the same conditions, either alpha-SNAP, other proteins apparently unrelated to vesicular transport (glyceraldehyde-3-phosphate dehydrogenase or lactic dehydrogenase) or even 3 mM magnesium ions can also cause lipid mixing. In contrast, neither NSF nor the other proteins nor magnesium had any significant fusogenic activity with liposomes composed of a biologically occurring mixture of lipids. A straightforward explanation is that the lipid composition chosen as optimal for NSF favors non-specific fusion because it is physically unstable when formed into liposomes. A variety of minor perturbations could then trigger coalescence.
Adenosine Triphosphatases↗
Telemetry as a new concept in long term monitoring of SIDS-risk infant.
Sudden Infant Death Syndrome (SIDS) is the most frequent cause of infant death within the period of 2 to 12 months in western countries. It has been found that a suit similar to that worn by the astronauts during the execution of experiments on the Spacelab Mission D-2 is a very simple and useful means to carry the sensors required to monitor vital signs of babies at risk. A small baby-suit has been developed with the same technology used for the Spacelab Mission. The baby s suit is equipped with similar sensors to record thoracic and abdominal respiratory movements as its big -space travel brother-. This is a typical example of a successful technology transfer from medical aerospace activities into fields of daily clinical routine. In addition to the above described sensors, ECG-electrodes were integrated, as well as sensors to record vascular oxygen saturation and the corresponding pulse curve, and the baby s movements. All these vital signs are registered by a medical monitor, and permanently stored and automatically analysed online. In case of a life-threatening situation the system alerts simultaneously the personal at hospital and the parents at home. The requisite software algorithms have been developed by DLR in Cooperation with the pediatricians of the Pediatric Hospital in Köln-Porz, Cologne. When the system registers an alteration of the parameters above described -as a signal of a change in the baby s health condition- all vital signs are transfered in real-time to the supervising hospital via radio data transmission devices, mobile phone or a fixed network phone. The parents are also alerted by the device, and they can carry out the necessary reanimation procedures in case of an emergency. Parents will be trained in such actions when newborns must to be monitored. But nevertheless, they are guided and tele-assisted by an expert via telephone during the action. A clinical field trial, that will start in December 1999 at the Pediatric Hospital in Köln-Porz, Cologne, will evaluate the benefits of teleprotection by home monitoring of SIDS risk-babies.
Humans↗