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Showing papers by "University of Marburg published in 1999"


Journal ArticleDOI
TL;DR: General rules for the structural basis of substrate recognition in adenylation domains of multimodular peptide synthetases can be used to rationally alter the specificity of adenyation domains and to predict from the primary sequence the Specificity of biochemically uncharacterized adenYLation domains.

1,136 citations


Journal ArticleDOI
TL;DR: The LMW-PEI described here is a new, highly efficient, and non-cytotoxic vector with a favorable efficiency/toxicity profile for gene therapeutic applications.
Abstract: Purpose. Low molecular weight branched polyethylenimine (LMW-PEI) was synthesized and studied as a DNA carrier for gene delivery with regard to physico-chemical properties, cytotoxicity, and transfection efficiency.

1,131 citations


Journal ArticleDOI
01 Oct 1999-Gene
TL;DR: Molecular, genetic and biochemical analyses demonstrated that Sp2, Sp3 and Sp4 are not simply functional equivalents of Sp1.

1,109 citations


Journal ArticleDOI
TL;DR: It is demonstrated that mitochondria perform an essential role in the synthesis of both intra‐ and extra‐mitochondrial Fe/S proteins, with potential relevance for an iron‐storage disease and the control of cellular iron uptake.
Abstract: Iron-sulfur (Fe/S) cluster-containing proteins catalyse a number of electron transfer and metabolic reactions. Little is known about the biogenesis of Fe/S clusters in the eukaryotic cell. Here, we demonstrate that mitochondria perform an essential role in the synthesis of both intra- and extra-mitochondrial Fe/S proteins. Nfs1p represents the yeast orthologue of the bacterial cysteine desulfurase NifS that initiates biogenesis by producing elemental sulfur. The matrix-localized protein is required for synthesis of both mitochondrial and cytosolic Fe/S proteins. The ATP-binding cassette (ABC) transporter Atm1p of the mitochondrial inner membrane performs an essential function only in the generation of cytosolic Fe/S proteins by mediating export of Fe/S cluster precursors synthesized by Nfs1p and other mitochondrial proteins. Assembly of cellular Fe/S clusters constitutes an indispensable biosynthetic task of mitochondria with potential relevance for an iron-storage disease and the control of cellular iron uptake.

677 citations


Journal ArticleDOI
08 Jul 1999-Nature
TL;DR: Comparisons of behavioural and electrophysiological indices of spatial tuning within central and peripheral auditory space in congenitally blind and normally sighted but blindfolded adults test the hypothesis that the effects of visual deprivation might be more pronounced for processing peripheral sounds.
Abstract: Despite reports of improved auditory discrimination capabilities in blind humans1,2,3 and visually deprived animals4, there is no general agreement as to the nature or pervasiveness of such compensatory sensory enhancements5. Neuroimaging studies have pointed out differences in cerebral organization between blind and sighted humans6,7,8,9,10,11,12, but the relationship between these altered cortical activation patterns and auditory sensory acuity remains unclear. Here we compare behavioural and electrophysiological indices of spatial tuning within central and peripheral auditory space in congenitally blind and normally sighted but blindfolded adults to test the hypothesis (raised by earlier studies of the effects of auditory deprivation on visual processing13,14) that the effects of visual deprivation might be more pronounced for processing peripheral sounds. We find that blind participants displayed localization abilities that were superior to those of sighted controls, but only when attending to sounds in peripheral auditory space. Electrophysiological recordings obtained at the same time revealed sharper tuning of early spatial attention mechanisms in the blind subjects. Differences in the scalp distribution of brain electrical activity between the two groups suggest a compensatory reorganization of brain areas in the blind that may contribute to the improved spatial resolution for peripheral sound sources.

639 citations


Journal ArticleDOI
TL;DR: Recent advances that have been directed towards understanding the biological role of transcription factors are summarized and discussed.
Abstract: One of the most common regulatory elements is the GC box and the related GT/CACC box, which are widely distributed in promoters, enhancers and locus control regions of housekeeping as well as tissue-specific genes. For long it was generally thought that Sp1 is the major factor acting through these motifs. Recent discoveries have shown that Sp1 is only one of many transcription factors binding and acting through these elements. Sp1 simply represents the first identified and cloned protein of a family of transcription factors characterised by a highly conserved DNA-binding domain consisting of three zinc fingers. Currently this new family of transcription factors has at least 16 different mammalian members. Here, we will summarise and discuss recent advances that have been directed towards understanding the biological role of these proteins.

628 citations


Journal ArticleDOI
TL;DR: These findings place proline isomerases at the intersection of protein folding, signal transduction, trafficking, assembly and cell cycle regulation.
Abstract: Cyclosporine A therapy for prophylaxis against graft rejection revolutionized human organ transplantation. The immunosuppressant drugs cyclosporin A (CsA), FK506 and rapamycin block T-cell activation by interfering with the signal transduction pathway. The target proteins for CsA and FK506 were found to be cyclophilins and FK506-binding proteins, (FKBPs), respectively. They are unrelated in primary sequence, although both are peptidyl-prolyl cis-trans isomerases catalyzing the interconversion of peptidyl-prolyl imide bonds in peptide and protein substrates. However, the prolyl isomerase activity of these proteins is not essential for their immunosuppressive effects. Instead, the specific surfaces of the cyclophilin-CsA and FKBP-FK506 complexes mediate the immunosuppressive action. Moreover, the natural cellular functions of all but a few remain elusive. In some cases it could be demonstrated that prolyl isomerization is the rate-limiting step in protein folding in vitro, but many knockout mutants of single and multiple prolyl isomerases were viable with no detectable phenotype. Even though a direct requirement for in vivo protein folding could not be demonstrated, some important natural substrates of the prolyl isomerases are now known, and they demonstrate the great variety of prolyl isomerization functions in the living cell: (i) A human cyclophilin binds to the Gag polyprotein of the human immunodeficiency virus-1 (HIV-1) virion and was found to be essential for infection with HIV to occur, probably by removal of the virion coat. (ii) Together with heat shock protein (HSP) 90, a member of the chaperone family, high molecular weight cyclophilins and FKBPs bind and activate steroid receptors. This example also demonstrates that prolyl isomerases act together with other folding enzymes, for example the chaperones, and protein disulfide isomerases. (iii) An FKBP was found to act as a modulator of an intracellular calcium release channel. (iv) Along with the cyclophilins and FKBPs, a third class of prolyl isomerases exist, the parvulins. The human parvulin homologue Pin1 is a mitotic regulator essential for the G2/M transition of the eukaryotic cell cycle. These findings place proline isomerases at the intersection of protein folding, signal transduction, trafficking, assembly and cell cycle regulation.

623 citations


Journal ArticleDOI
01 Jan 1999-Gut
TL;DR: Intravenous infusions of GLP-1 decrease spontaneous food intake even at physiological plasma concentrations, implying an important role for GLp-1 in the regulation of the early satiety response in humans.
Abstract: Background/Aims Studies in animals suggest a physiological role for glucagon-like peptide-1-(7–36)-amide (GLP-1) in regulating satiety. The role of GLP-1 in regulating food intake in man has, however, not been investigated. Subjects—Sixteen healthy male subjects were examined in a double blind placebo controlled fashion. Methods The effect of graded intravenous doses (0, 0.375, 0.75, and 1.5 pmol/kg/min) of synthetic human GLP-1 on food intake and feelings of hunger and satiety was tested in healthy volunteers. Results Graded GLP-1 infusions resulted in a dose dependent reduction in food intake (maximal inhibition 35%, p v control) and a similar reduction in calorie intake (32%; p Conclusions Intravenous infusions of GLP-1 decrease spontaneous food intake even at physiological plasma concentrations, implying an important role for GLP-1 in the regulation of the early satiety response in humans.

598 citations


Journal ArticleDOI
TL;DR: In this paper, the authors review the nonlinear optical properties of semiconductor quantum wells that are grown inside high-Q Bragg-mirror microcavities and explain the Coulomb interacting electron-hole system in the quantum well.
Abstract: The authors review the nonlinear optical properties of semiconductor quantum wells that are grown inside high-Q Bragg-mirror microcavities. Light-matter coupling in this system is particularly pronounced, leading in the linear regime to a polaritonic mixing of the excitonic quantum well resonance and the single longitudinal cavity mode. The resulting normal-mode splitting of the optical resonance is observed in reflection, transmission, and luminescence experiments. In the nonlinear regime the strong light-matter coupling influences the excitation-dependent bleaching of the normal-mode resonances for nonresonant excitation, leads to transient saturation and normal-mode oscillations for resonant pulsed excitation and is responsible for the density-dependent signatures in the luminescence characteristics. These and many more experimental observations are summarized and explained in this review using a microscopic theory for the Coulomb interacting electron-hole system in the quantum well that is nonperturbatively coupled to the cavity light field.

492 citations


Journal ArticleDOI
TL;DR: A marked effect of GLP-1 on appetite is demonstrated by showing enhanced satiety and reduced energy intake in patients with diabetes type 2.
Abstract: Glucagon-like peptide-1-(7-36) amide (GLP-1) is an incretin hormone of the enteroinsular axis. Recent experimental evidence in animals and healthy subjects suggests that GLP-1 has a role in controlling appetite and energy intake in humans. We have therefore examined in a double-blind, placebo-controlled, crossover study in 12 patients with diabetes type 2 the effect of intravenously infused GLP-1 on appetite sensations and energy intake. On 2 days, either saline or GLP-1 (1.5 pmol. kg-1. min-1) was given throughout the experiment. Visual analog scales were used to assess appetite sensations; furthermore, food and fluid intake of a test meal were recorded, and blood was sampled for analysis of plasma glucose and hormone levels. GLP-1 infusion enhanced satiety and fullness compared with placebo (P = 0.028 for fullness and P = 0.026 for hunger feelings). Energy intake was reduced by 27% by GLP-1 (P = 0.034) compared with saline. The results demonstrate a marked effect of GLP-1 on appetite by showing enhanced satiety and reduced energy intake in patients with diabetes type 2.

487 citations


Journal ArticleDOI
TL;DR: It is postulated that apoE promotes both the deposition and fibrillization of Abeta, ultimately affecting clearance of protease-resistant Abeta/apoE aggregates.
Abstract: We quantified the amount of amyloid beta-peptide (Abeta) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP(V717F+/-) TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP(V717F+/-) Apoe(-/-) TG mice as old as 22 mo of age, whereas age-matched APP(V717F +/-) Apoe(+/-) and Apoe(+/+) TG mice display abundant amyloid deposition. The amount of Abeta immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe(+/+) > Apoe(+/-) >> Apoe(-/-)), and no Abeta immunoreactivity was detected in the cerebral cortex of APP(V717F+/-) Apoe(-/-) TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both Abeta(1-40) and Abeta(1-42) immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP(V717F) TG mice. ApoE immunoreactivity was detected in a subset of Abeta immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP(V717F) transgene nor its processing to Abeta peptide(s), we postulate that apoE promotes both the deposition and fibrillization of Abeta, ultimately affecting clearance of protease-resistant Abeta/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.

Journal ArticleDOI
TL;DR: In this article, a detailed understanding of the electronic structure of a reaction system can help recognize certain characteristics of the process, yielding valuable mechanistic concepts, such as the E2−SN2 spectrum.
Abstract: On the basis of Kohn–Sham density functional (DFT) investigations on elementary organic and organometallic reactions, we show how a detailed understanding of the electronic structure of a reaction system can help recognize certain characteristics of the process, yielding valuable mechanistic concepts. The concept of the base as a selective catalyst in E2 eliminations, for example, leads to a straightforward explanation for the general preference for anti over syn stereochemistry in base-induced elimination reactions. Furthermore, electronic structure considerations provide the so-called E2–SN2 mechanistic spectrum, in terms of which one can interpret and understand the competition between elimination and substitution reactions and the shift, on solvation, of the reactivity from E2 to SN2. In addition, mechanistic concepts from organometallic and organic chemistry are linked as we argue that oxidative addition may be conceived, in some respect, as the organometallic analog of the frontside SN2 substitution. Finally, we introduce the ideas of “activation strain” of and “transition state interaction” between the deformed reactants in the activated complex, which together determine the activation energy, ΔE*=ΔE+ΔE. They prove to be helpful conceptual tools for understanding in detail how activation barriers and relative efficiencies of competing reaction mechanisms arise and how they may be affected (e.g., by changing reactants or by solvation). © 1999 John Wiley & Sons, Inc. J Comput Chem 20: 114–128, 1999

Journal ArticleDOI
TL;DR: The data indicate that mutations in the MC4-R are not uncommon, and support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined.
Abstract: The melanocortin-4 receptor gene (MC4-R) has been implicated in weight regulation. Recently, two independent groups reported frameshift mutations associated with a dominant form of obesity (1, 2). We screened the coding region of the MC4-R in 306 extremely obese children and adolescents (mean body mass index: BMI 34.4 +/- 6.6 kg/m2), 25 healthy underweight students (mean BMI 17.1 +/- 0.8 kg/m2), 52 normal weight individuals (mean BMI 22.0 +/- 1.0 kg/m2), 51 inpatients with anorexia nervosa (AN, DSM IV criteria, mean BMI 14.3 +/- 1.5 kg/m2) and 27 patients with bulimia nervosa (BN, DSM IV criteria, mean BMI 21.7 +/- 5.8 kg/m2) by single strand conformation polymorphism analysis (SSCP). Several mutations were identified, including the frameshift mutation described (1). The mutations were as follows: a) The deletion of 4 bp (delta of CTCT at codon 211) results in a frameshift, thus rendering a truncated protein. This mutation has been assumed to be associated with dominantly-inherited morbid obesity in humans (1). Both the index patient (BMI 42.06 kg/m2, height 171 cm, age 19.6 years) and her mother (BMI 37.55 kg/m2, height 164 cm, age 42.5 years) were heterozygous for the deletion. b) A nonsense mutation at position 35 of the MC4-R was detected in two obese probands (BMI 31.29 kg/m2 and BMI 45.91 kg/m2). This mutation leads to a truncated protein that encompasses the N-terminal extracellular domain. Both carriers additionally showed (c) a missense mutation (Asp-37-Val). In both of these cases Tyr-35-Stop and Asp-37-Val were maternally transmitted, thus these variations form a haplotype. d) e) A male obese proband harbored two missense mutations (Ser-30-Phe, Gly-252-Ser). f)-i) Four different missense mutations (Pro-78-Leu, Thr-112-Met, Arg-165-Trp, Ile-317-Thr) were detected in four different male probands, respectively. All of these mutations (a to i) were found solely in extremely obese individuals whose BMIs were all above the 99th percentile. j) A silent mutation (C-579-T, Val-193-Val) was detected in a male underweight individual. k) A previously described polymorphism (Val-103-Ile; 3) was detected with similar frequencies in all different study groups. 1) We identified a novel polymorphism (Ile-251-Leu) with similar allele frequencies in all groups under study. In conclusion, our data indicate that mutations in the MC4-R are not uncommon. Whereas our data support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined.

Journal ArticleDOI
05 Feb 1999-Cell
TL;DR: Crystal structures suggest that the seven Sm proteins could form a closed ring and the snRNAs may be bound in the positively charged central hole.

Journal ArticleDOI
TL;DR: Three-dimensional quantitative structure-activity relationship methods were applied using a training set of 72 inhibitors of the benzamidine type with respect to their binding affinities toward thrombin, trypsin, and factor Xa to yield statistically reliable models of good predictive power.
Abstract: Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied using a training set of 72 inhibitors of the benzamidine type with respect to their binding affinities (Ki values) toward thrombin, trypsin, and factor Xa to yield statistically reliable models of good predictive power. Two methods were compared: the widely used comparative molecular field analysis (CoMFA) and the recently reported CoMSIA approach (comparative molecular similarity indices analysis). CoMSIA produced significantly better results for all correlations. Furthermore, in contrast to CoMFA, CoMSIA is not sensitive to changes in orientation of the superimposed molecules in the lattice. The correlation results obtained by CoMSIA were graphically interpreted in terms of field contribution maps allowing physicochemical properties relevant for binding to be easily mapped back onto molecular structures. The advantage of this feature is demonstrated using the maps to design new molecules. Finally, the CoMSIA method was applied to elucidate structural features among ligands which are responsible for affinity differences toward thrombin and trypsin. These selectivity-determining features were interpreted graphically in terms of spatial regions responsible for affinity discrimination. Such indicators are highly informative for the lead optimization process with respect to selectivity enhancement.

Journal ArticleDOI
TL;DR: To compare the replication and transcription strategies of both viruses, an artificial replication system based on the vaccinia virus T7 expression system was established for EBOV and it was observed that neither MBGV nor E BOV were able to replicate the heterologous minigenomes.
Abstract: The members of the family Filoviridae, Marburg virus (MBGV) and Ebola virus (EBOV), are very similar in terms of morphology, genome organization, and protein composition. To compare the replication and transcription strategies of both viruses, an artificial replication system based on the vaccinia virus T7 expression system was established for EBOV. Specific transcription and replication of an artificial monocistronic minireplicon was demonstrated by reporter gene expression and detection of the transcribed and replicated RNA species. As it was shown previously for MBGV, three of the four EBOV nucleocapsid proteins, NP, VP35, and L, were essential and sufficient for replication. In contrast to MBGV, EBOV-specific transcription was dependent on the presence of the fourth nucleocapsid protein, VP30. When EBOV VP30 was replaced by MBGV VP30, EBOV-specific transcription was observed but with lower efficiency. Exchange of NP, VP35, and L between the two replication systems did not lead to detectable reporter gene expression. It was further observed that neither MBGV nor EBOV were able to replicate the heterologous minigenomes. A chimeric minigenome, however, containing the EBOV leader and the MBGV trailer was encapsidated, replicated, transcribed, and packaged by both viruses.

Journal ArticleDOI
TL;DR: This research presents a novel and scalable approach to cardiology called “SmartCardiology,” which combines real-time, mobile, and 3D image analysis of the response of the autonomic nervous system to foreign substances.
Abstract: *International Centre for Genetic Engineering and Biotechnology, and **Department of Cardiology, Ospedale Maggiore, Trieste, Italy; †Department of Internal Medicine & Cardiology, Hospitals of the Philipps-University, Marburg, Germany; ‡Department of Cardiological Sciences, St. George’s Hospital Medical School, London, U.K.; §Institut de Myologie, QDepartment of Cardiology, Q¶Lab. Génétique et Insuffisance Cardiaque, Association Claude Bernard, Groupe Hospitalier Pitié-Salpétriere, Paris, France

Journal ArticleDOI
TL;DR: The results of the activation study indicate that different functions in pain processing can be attributed to different brain regions.
Abstract: Brain imaging with positron emission tomography has identified some of the principal cerebral structures of a central network activated by pain. To discover whether the different cortical and subcortical areas process different components of the multidimensional nature of pain, we performed a regression analysis between noxious heat-related regional blood flow increases and experimental pain parameters reflecting detection of pain, encoding of pain intensity, as well as pain unpleasantness. The results of our activation study indicate that different functions in pain processing can be attributed to different brain regions; ie, the gating function reflected by the pain threshold appeared to be related to anterior cingulate cortex, the frontal inferior cortex, and the thalamus, the coding of pain intensity to the periventricular gray as well as to the posterior cingulate cortex, and the encoding of pain unpleasantness to the posterior sector of the anterior cingulate cortex.

Journal ArticleDOI
TL;DR: This is a review of recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients on Proteus syndrome held in March 1998 at the National Institutes of Health.
Abstract: Proteus syndrome is a complex disorder comprising malformations and overgrowth of multiple tissues. The disorder is highly variable and appears to affect patients in a mosaic manner. This intrinsic variability has led to diagnostic confusion associated with a dearth of longitudinal data on the natural history of Proteus syndrome. To clarify some of these issues, a workshop on Proteus syndrome was held in March 1998 at the National Institutes of Health, and participants developed recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients. This is a review of those recommendations.

Journal ArticleDOI
TL;DR: Based on current methods of bone ing growth assessment, this article comparatively reviews and discusses the results of experimental studies with the objective of determining local and systemic factors that enhance bone ingrowth fixation.
Abstract: The term osseointegration referred originally to an intimate contact of bone tissue with the surface of a titanium implant; the term bone ingrowth refers to bone formation within an irregular (beads, wire mesh, casting voids, cut grooves) surface of an implant. The section dealing with the historical background describes the development of macroporous, microporous, and textured surfaces with an emphasis on the evolution of porous and textured metal surfaces. The principal requirements for osseointegration and bone ingrowth are systematically reviewed as follows: i) the physiology of osseointegration and bone ingrowth, including biomaterial biocompatibility with respect to cellular and matrix response at the interface; ii) the implant surface geometry characteristics; iii) implant micromotion and fixation modes; and iv) the implant-bone interface distances. Based on current methods of bone ingrowth assessment, this article comparatively reviews and discusses the results of experimental studies with the objective of determining local and systemic factors that enhance bone ingrowth fixation.

Journal ArticleDOI
TL;DR: The existence of initially antibody-positive HHCs suggests that mild cases of Ebola virus infection occurred and that the full extent of the EHF epidemic was probably underestimated.
Abstract: A cohort of convalescent Ebola hemorrhagic fever (EHF) patients and their household contacts (HHCs) were studied prospectively to determine if convalescent body fluids contain Ebola virus and if secondary transmission occurs during convalescence. Twenty-nine EHF convalescents and 152 HHCs were monitored for up to 21 months. Blood specimens were obtained and symptom information was collected from convalescents and their HHCs; other body fluid specimens were also obtained from convalescents. Arthralgias and myalgia were reported significantly more often by convalescents than HHCs. Evidence of Ebola virus was detected by reverse transcription-polymerase chain reaction in semen specimens up to 91 days after disease onset; however, these and all other non-blood body fluids tested negative by virus isolation. Among 81 initially antibody negative HHCs, none became antibody positive. Blood specimens of 5 HHCs not identified as EHF patients were initially antibody positive. No direct evidence of convalescent-to-HHC transmission of EHF was found, although the semen of convalescents may be infectious. The existence of initially antibody-positive HHCs suggests that mild cases of Ebola virus infection occurred and that the full extent of the EHF epidemic was probably underestimated.

Journal ArticleDOI
TL;DR: The administration of anti-MIF monoclonal antibodies to mice was found to reduce significantly the growth and the vascularization of the 38C13 B cell lymphoma, and suggest a new target for the development ofAnti-neoplastic agents that inhibit tumor neovascularization.
Abstract: Macrophage migration inhibitory factor (MIF) has been shown to counterregulate glucocorticoid action and to play an essential role in the activation of macrophages and T cells in vivo. MIF also may function as an autocrine growth factor in certain cell systems. We have explored the role of MIF in the growth of the 38C13 B cell lymphoma in C3H/HeN mice, a well-characterized syngeneic model for the study of solid tumor biology. Tumor-bearing mice were treated with a neutralizing anti-MIF monoclonal antibody and the tumor response assessed grossly and histologically. Tumor capillaries were enumerated by immunohistochemistry and analyzed for MIF expression. The effect of MIF on endothelial cell proliferation was studied in vitro, utilizing both specific antibody and antisense oligonucleotide constructs. The role of MIF in angiogenesis also was examined in a standard Matrigel model of new blood vessel formation in vivo. The administration of anti-MIF monoclonal antibodies to mice was found to reduce significantly the growth and the vascularization of the 38C13 B cell lymphoma. By immunohistochemistry, MIF was expressed predominantly within the tumor-associated neovasculature. Cultured microvascular endothelial cells, but not 38C13 B cells, produced MIF protein and required its activity for proliferation in vitro. Anti-MIF monoclonal antibody also was found to markedly inhibit the neovascularization response elicited by Matrigel implantation. These data significantly expand the role of MIF in host responses, and suggest a new target for the development of anti-neoplastic agents that inhibit tumor neovascularization.

Book ChapterDOI
TL;DR: Molecular analyses of the genomes clearly demonstrated that filoviruses are the closest relatives to Rhabdoviridae and Paramyxovirids, and may be a spectrum of genetic variants selected by the host for different transmissibility, virulence, and other biological properties.
Abstract: Publisher Summary Filoviruses are among the most pathogenic of human viruses. They are classified as “Biological Level 4” agents (WHO; Risk Group 4) based on their high mortality rate, person-to-person transmission, potential aerosol infectivity, and absence of vaccines and chemotherapy. Molecular analyses of the genomes clearly demonstrated that filoviruses are the closest relatives to Rhabdoviridae and Paramyxoviridae. All nonsegmented negative-stranded (NNS) RNA viruses share a similar genome organization, with conserved regions at both ends encoding the core and L proteins surrounding a variable part in the middle encoding the envelope proteins. Direct detection of virus antigen, virus particles, and viral RNA can be achieved by several assays. Electron microscopy has been particularly useful in the diagnosis of filovirus infections. Viral structures can be visualized by negative contrast electron microscopy after ultracentrifugation and fixation of initial passage cell culture supernatants. Limited knowledge of the epidemiology and clinical picture of filoviral hemorrhagic fever (HP) and inexperience in diagnosing cases and in case in management magnify the danger of an introduction. Filoviruses—like other RNA viruses—presumably have a potential for rapid evolution because of an inherently high error rate of the virus encoded polymerase and a lack of repair mechanisms. The consequence may be a spectrum of genetic variants that are selected by the host for different transmissibility, virulence, and other biological properties.

Journal ArticleDOI
TL;DR: Comparative molecular field analysis has been applied to a data set of thermolysin inhibitors and the results obtained demonstrate the prediction power of the CoMSIA method.
Abstract: Comparative molecular field analysis has been applied to a data set of thermolysin inhibitors. Fields expressed in terms of molecular similarity indices (CoMSIA) have been used instead of the usually applied Lennard-Jones- and Coulomb-type potentials (CoMFA). Five different properties, assumed to cover the major contributions responsible for ligand binding, have been considered: steric, electrostatic, hydrophobic, and hydrogen-bond donor or acceptor properties. The statistical evaluation of the field properties by PLS analysis reveals a similar predictive potential to CoMFA. However, significantly improved and easily interpretable contour maps are obtained. The features in these maps intuitively suggest where to modify a molecular structure in terms of physicochemical properties and functional groups in order to improve its binding affinity. They can also be interpreted with respect to the known structural protein environment of thermolysin. Most of the highlighted regions in the maps are mirrored by features in the surrounding environment required for binding. Using the derived correlation model, different members of a combinatorial library designed for thermolysin inhibition have been scored for affinity. The results obtained demonstrate the prediction power of the CoMSIA method.

Journal ArticleDOI
25 Nov 1999-Nature
TL;DR: A mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes is proposed, on the basis of immersion of hydrophobic residues at the apices of these loops in the apolar membrane core and specific interactions with phosphatidylserine head groups in the groove enclosed by these loops.
Abstract: Rapid and controlled clot formation is achieved through sequential activation of circulating serine proteinase precursors on phosphatidylserine-rich procoagulant membranes of activated platelets and endothelial cells. The homologous complexes Xase and prothrombinase, each consisting of an active proteinase and a non-enzymatic cofactor, perform critical steps within this coagulation cascade. The activated cofactors VIIIa and Va, highly specific for their cognate proteinases, are each derived from precursors with the same A1-A2-B-A3-C1-C2 architecture. Membrane binding is mediated by the C2 domains of both cofactors. Here we report two crystal structures of the C2 domain of human factor Va. The conserved beta-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly different conformations in the two crystal forms. We propose a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes, on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.

Journal ArticleDOI
TL;DR: Many low-molecular-weight peptides of microbial origin are synthesized nonribosomally on large multifunctional proteins, termed peptide synthetases, in which several defined domains catalyze specific reactions of peptide synthesis.


Journal ArticleDOI
TL;DR: From the exceedingly high rate of smokers among patients with this condition, it is concluded that cigarette smoking is a major triggering factor of hidradenitis suppurativa.
Abstract: Background: Hidradenitis suppurativa is a chronic inflammatory skin disease involving the axillary, inguinal and anogenital regions and sometimes, in addition, the submammary or sac

Journal Article
TL;DR: The primary structure of this novel MBL-associated plasma protein of 19 kDa is presented, and it is demonstrated that MAp19 and MASP-2 are encoded by two different mRNA species generated by alternative splicing/polyadenylation from one structural gene.
Abstract: Mannan-binding lectin (MBL) forms a multimolecular complex with at least two MBL-associated serine proteases, MASP-1 and MASP-2. This complex initiates the MBL pathway of complement activation by binding to carbohydrate structures present on bacteria, yeast, and viruses. MASP-1 and MASP-2 are composed of modular structural motifs similar to those of the C1q-associated serine proteases C1r and C1s. Another protein of 19 kDa with the same N-terminal sequence as the 76-kDa MASP-2 protein is consistently detected as part of the MBL/MASP complex. In this study, we present the primary structure of this novel MBL-associated plasma protein of 19 kDa, MAp19, and demonstrate that MAp19 and MASP-2 are encoded by two different mRNA species generated by alternative splicing/polyadenylation from one structural gene.

Journal ArticleDOI
TL;DR: In this paper, the authors investigated the environmental limits to cyanobacterial calcification in fast-flowing streams and found that cyanobacteria preferentially utilize bicarbonate and sheath impregnation by calcium carbonate even where the annual WATEQ4F Saturation Index exceeds 0.8.