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Biomedical subjects

B Neumann

Publications and source records attributed to B Neumann.

At least 19 recordsLinked to original sources
PubMed2005

Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans.

A key challenge of functional genomics today is to generate well-annotated data sets that can be interpreted across different platforms and technologies. Large-scale functional genomics data often fail to connect to standard experimental approaches of gene characterization in individual laboratories. Furthermore, a lack of universal annotation standards for phenotypic data sets makes it difficult to compare different screening approaches. Here we address this problem in a screen designed to identify all genes required for the first two rounds of cell division in the Caenorhabditis elegans embryo. We used RNA-mediated interference to target 98% of all genes predicted in the C. elegans genome in combination with differential interference contrast time-lapse microscopy. Through systematic annotation of the resulting movies, we developed a phenotypic profiling system, which shows high correlation with cellular processes and biochemical pathways, thus enabling us to predict new functions for previously uncharacterized genes.

Animals↗
PubMed2005

Centrality dependence of charged-particle pseudorapidity distributions from d + Au collisions at sqrt[sNN] = 200 GeV.

Charged-particle pseudorapidity densities are presented for the d + Au reaction at sqrt[s(NN)] = 200 GeV with -4.2 < or = eta < or = 4.2. The results, from the BRAHMS experiment at BNL Relativistic Heavy-Ion Collider, are shown for minimum-bias events and 0%-30%, 30%-60%, and 60%-80% centrality classes. Models incorporating both soft physics and hard, perturbative QCD-based scattering physics agree well with the experimental results. The data do not support predictions based on strong-coupling, semiclassical QCD. In the deuteron-fragmentation region the central 200 GeV data show behavior similar to full-overlap d+Au results at sqrt[s(NN)] = 19.4 GeV.

Journal Article↗
PubMed2004

Evolution of the nuclear modification factors with rapidity and centrality in d + Au collisions at (sqrt)[N(S)N]=200 GeV.

We report on a study of the transverse momentum dependence of nuclear modification factors R(dAu) for charged hadrons produced in deuteron + gold collisions at sqrt[s(NN)]=200 GeV, as a function of collision centrality and of the pseudorapidity (eta=0, 1, 2.2, 3.2) of the produced hadrons. We find a significant and systematic decrease of R(dAu) with increasing rapidity. The midrapidity enhancement and the forward rapidity suppression are more pronounced in central collisions relative to peripheral collisions. These results are relevant to the study of the possible onset of gluon saturation at energies reached at BNL RHIC.

Journal Article↗
PubMed2004

RGD-mutants of B-lymphotropic polyomavirus capsids specifically bind to alpha(v)beta3 integrin.

Integrins are a family of cell surface proteins that function as receptors for extracellular matrix ligands and for some viruses. A subset of integrins recognises peptide sequences containing arginine-glycine-aspartic acid (RGD) motifs as ligands. The B-lymphotropic polyomavirus (LPV) has a non-enveloped capsid that recognises a sialylated cell surface receptor. To change the receptor binding specificity we have replaced sets of three amino acids in three predicted surface loops of the major capsid protein VP1 of the B-lymphotropic polyomavirus LPV by RGD. Ten mutants gave rise to the expected 40 kDa VP1 protein upon expression from a baculovirus vector in insect cells. Five of the VP1 mutants representing all three surface loops have retained the ability to spontaneously assemble to capsids in the nuclei of the insect cells. Structural changes of the mutant capsid surface were shown by differential reactivity with a set of 7 neutralising monoclonal antibodies that recognise conformational surface epitopes of wildtype LPV virions. In addition all mutant capsids had lost specific binding to the LPV receptor. Three mutant capsids of one loop (BC) showed specific binding to alpha(v)beta3 integrin but not to integrins alpha(v)beta5, alpha(v)beta6, or to alpha(IIb)beta3 known also to recognise RGD containing peptide sequences. This selective binding of the mutant capsids could be inhibited by synthetic peptides that specifically bind to alpha(v)beta3 integrin with IC50 values between 10 and 40 nM.

Amino Acid Motifs↗
PubMed2003

Transverse-momentum spectra in Au+Au and d+Au collisions at sqrt[s(NN)]=200 GeV and the pseudorapidity dependence of high-p(T) suppression.

We present spectra of charged hadrons from Au+Au and d+Au collisions at sqrt[s(NN)]=200 GeV measured with the BRAHMS experiment at RHIC. The spectra for different collision centralities are compared to spectra from p+(-)p collisions at the same energy scaled by the number of binary collisions. The resulting ratios (nuclear modification factors) for central Au+Au collisions at eta=0 and eta=2.2 evidence a strong suppression in the high p(T) region (>2 GeV/c). In contrast, the d+Au nuclear modification factor (at eta=0) exhibits an enhancement of the high p(T) yields. These measurements indicate a high energy loss of the high p(T) particles in the medium created in the central Au+Au collisions. The lack of suppression in d+Au collisions makes it unlikely that initial state effects can explain the suppression in the central Au+Au collisions.

Journal Article↗
PubMed2002

Measurement of long-range repulsive forces between charged particles at an oil-water interface.

Using a laser tweezers method, we have determined the long-range repulsive force as a function of separation between two charged, spherical polystyrene particles (2.7 microm diameter) present at a nonpolar oil-water interface. At large separations (6 to 12 microm between particle centers) the force is found to decay with distance to the power -4 and is insensitive to the ionic strength of the aqueous phase. The results are consistent with a model in which the repulsion arises primarily from the presence of a very small residual electric charge at the particle-oil interface. This charge corresponds to a fractional dissociation of the total ionizable (sulfate) groups present at the particle-oil surface of approximately 3 x 10(-4).

Journal Article↗
PubMed2002

[Radioprotective effectiveness of amifostine on the salivary glands of the rat during fractionated irradiation].

BACKGROUND: The aim of this study was to evaluate the cytoprotective potency of amifostine during a fractioned irradiation of salivary glands but also on the tumor response of rhabdomyosarcomas R1H in rats. METHOD: The head-neck-area of male WAG/RijH rats and the tumor in the flank were irradiated with 60Co-gamma-rays (60 Gy/30 f/6 weeks). Amifostine (250 mg/m2) was applicated 15 min before irradiation. The control group was treated with an equal volume of physiologic sodium chloride. The salivary glands were exstirpated and examined histopathologically. Tumour volume was measured, the body-weight of rats determined. RESULTS: A dose dependent radiosialadenitis developed in all salivary glands. Amifostine had no influence on the response of R1H tumours to radiation. The animal weight loss in the amifostine group was higher as compared to control group. CONCLUSIONS: No cytoprotective effects on acute toxicity of salivary glands of rats could be detected under irradiation with synchronous application of amifostine. In addition, no effects on tumor response were observed. The general animal constitution decreased by additional medication of amifostine.

Amifostine↗
PubMed2001

Reactivity of the inversely polarized phosphaalkenes RP=C(NMe2)2 (R = tBu, Me3Si, H) towards arylcarbene complexes [(CO)5M=C(oEt)Ar] (Ar= Ph, M = Cr, W; Ar = 2-MeC6H4, 2-MeOC6H4, M = W).

The reaction of the arylated Fischer carbene complexes [(CO)5M=C(OEt)Ar] (Ar=Ph; M = Cr, W; 2-MeC6H4; 2-MeOC6H; M = W) with the phosphaalkenes RP=C(NMe2), (R=tBu, SiMe3) afforded the novel phosphaalkene complexes [[RP=C(OEt)Ar]M(CO)5] in addition to the compounds [(RP=C(NMe2)2]M(CO)5]. Only in the case of the R = SiMe3 (E/Z) mixtures of the metathesis products were obtained. The bis(dimethylamino)methylene unit of the phosphaalkene precursor was incorporated in olefins of the type (Me2N)2C=C(OEt)(Ar). Treatment of [(CO)5W=C(OEt)(2-MeOC6H4)] with HP=C(NMe2)2 gave rise to the formation of an E/Z mixture of [[(Me2N)2CH-P=C(OEt)(2-MeOC6H4)]W(CO)5] the organophosphorus ligand of which formally results from a combination of the carbene ligand and the phosphanediyl [P-CH(NMe2)2]. The reactions reported here strongly depend on an inverse distribution of alpha-electron density in the phosphaalkene precursors (Pdelta Cdelta+), which renders these molecules powerfu] nucleophiles.

Journal Article↗
PubMed2001

Novel heterocyclic inhibitors of matrix metalloproteinases: three 6H-1,3,4-thiadiazines.

The title compounds, (2S)-N-[5-(4-chlorophenyl)-2,3-dihydro-6H-1,3,4-thiadiazin-2-ylidene]-2-[(phenylsulfonyl)amino]propanamide, C18H17ClN4O3S2, (I), (2R)-N-[5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)amino]propanamide, C18H17FN4O3S2, (II), and (2S)-N-[5-(5-chloro-2-thienyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)amino]propanamide, C16H15ClN4O3S3, (III), are potent inhibitors of matrix metalloproteinases. In all three compounds, the thiadiazine ring adopts a screw-boat conformation. The molecules of compound (I) show a short intramolecular N(Ala)-H...N(exo) hydrogen bond [N...N 2.661 (3) A] and are linked into a chain along the c axis by N(endo)-H...S(endo) and N(endo)-H...O(Ala) hydrogen bonds [N...S 3.236 (3) and N...O 3.375 (3) A] between neighbouring molecules. In compound (II), the molecules are connected antiparallel into a chain along the a axis by N(exo)-H...O(Ala) and N(Ala)-H...N(endo) hydrogen bonds [N...O 2.907 (6) and N...N 2.911 (6) A]. The molecules of compound (III) are dimerized antiparallel through N(exo)-H...N(endo) hydrogen bonds [N...N 2.956 (7) and 2.983 (7) A]. The different hydrogen-bonding patterns can be explained by an amido-imino tautomerism (prototropic shift) shown by different bond lengths within the 6H-1,3,4-thiadiazine moiety.

Crystallography, X-Ray↗
PubMed2000

Endotoxin-induced lung inflammation is independent of the complement membrane attack complex.

Several products of the activated complement system are known to modulate endothelial cell function in vitro. It has been shown that the membrane attack complex (MAC) (C5b-C9) can enhance tumor necrosis factor alpha (TNF-alpha)-induced expression of P- and E-selectin and intercellular adhesion molecule type 1 in cell cultures of human umbilical vein endothelial cells. In the present study the potential role of this synegism for lung injury during endotoxin-mediated septic shock in vivo was examined using a model of C6-deficient PVG (C-) (RT1(C)) rats and the congenic PVG (C+) (RT1(C)) strain. Following administration of a high (5 mg/kg) or low (0.5 mg/kg) dose of lipopolysaccharide (LPS) (Escherichia coli O55:B5), we determined the expression of cytokines, chemokines, and adhesion molecules as well as the recruitment of leukocytes in the lung. Challenge with intraperitoneal i.p. injections of LPS resulted in a strong induction of TNF-alpha, interleukin-1alpha/beta, cytokine-induced neutrophil chemoattractant, interferon-inducible protein 10, macrophage inflammatory proteins 1alpha and 2, macrophage chemotactic protein 1, and P-selectin. However, there were no significant differences between PVG (C-) and PVG (C+) rats. Immunoperoxidase staining showed a similar increase of lung infiltration by CD11b/c(+) leukocytes in both rat strains. We therefore conclude that the described synergism between TNF-alpha and the MAC of the complement system on the induction of endothelial adhesion molecules is dispensable for inflammatory processes during endotoxin-mediated septic shock in vivo.

Animals↗
PubMed1999

Casein kinase 2 binds and phosphorylates the nucleosome assembly protein-1 (NAP1) in Drosophila melanogaster.

The nucleosome assembly protein-1 (NAP1) was originally identified in HeLa cells as a factor facilitating the in vitro assembly of nucleosomes. However, in yeast cells NAP1 is required in the control of mitotic events induced by the Clb2/p34(CDC28). Here, we show that Drosophila NAP1 is a phosphoprotein that is associated with a kinase able to phosphorylate NAP1. By using an in-gel kinase assay we found that this kinase displays a molecular mass of 38 kDa. Following purification and peptide microsequencing, we identified the kinase phosphorylating NAP1 as the alpha subunit of casein kinase 2 (CK2). With the help of a series of NAP1 segments and synthetic peptides, we assigned the CK2 phosphorylation sites to residues Ser118, Thr120, and Ser284. Interestingly, Ser118 and Thr120 are located within a PEST domain, while Ser284 is adjacent to the nuclear localization signal. Substitution of the identified phosphoresidues by alanine was found to reduce considerably the ability of CK2 to phosphorylate NAP1. The enhanced ability of CK2 to phosphorylate phosphatase-treated NAP1 extracted from Drosophila embryos and the similar tryptic phospho-peptide pattern of in vivo labelled NAP1 and in vitro labelled NAP1 with CK2 indicate that NAP1 is a natural substrate of CK2. Further analysis revealed that both CK2alpha and beta subunits are associated with NAP1 but we found that only the catalytic alpha subunit establishes direct contact with NAP1 on two distinct domains of this protein. The location of CK2 phosphorylation sites in NAP1 suggests that their phosphorylation can contribute to a PEST-mediated protein degradation of NAP1 and the translocation of NAP1 between cytoplasm and nucleus.

Amino Acid Motifs↗
PubMed1999

Mechanisms of acute inflammatory lung injury induced by abdominal sepsis.

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.

Abdomen↗
PubMed1998

Modulation of the activation status of Stat5a during LIF-induced differentiation of M1 myeloid leukemia cells.

Treatment of M1 myeloid leukemia cells with leukemia inhibitory factor (LIF) causes activation of transcription factors Stat1, Stat3 and Stat5a (signal transducers and activators of transcription). DNA-binding of Stat proteins was detectable for extended periods of time in LIF-treated M1 cells, which simultaneously underwent terminal differentiation. The relative composition of Stat factors in the protein-DNA complexes changed during time. Whereas Stat3 was activated up to 36 h during treatment with LIF, Stat5a was activated only short-termed. Similarly, high expression of the immediate early gene CIS (cytokine-inducible SH2-containing protein), a known target gene of Stat5 in hematopoietic cells, occurred only during the onset of differentiation. This suggests a role of Stat5a in the early phase of LIF-induced differentiation and growth arrest of M1 cells.

Animals↗
PubMed1998

Distinct functions of interferon-gamma for chemokine expression in models of acute lung inflammation.

Challenge of the immune system with bacterial superantigens or endotoxin induces the systemic release of cytokines followed by lethal septic shock. The lung is particularly susceptible to systemic toxin exposure resulting in acute leucocyte infiltration and vascular damage. In the present study, the functions of interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) for chemokine regulation during acute lung inflammation were examined. Following administration of the superantigen, staphylococcal enterotoxin B (SEB), lung mRNA levels of the chemokines cytokine-induced neutrophil chemo-attractant (KC), lipopolysaccharide-induced CXC chemokine (LIX), macrophage chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha and MIP-2 were increased to a similar extent both in controls and in mice deficient for the IFN-gamma or 55 000 MW TNF receptors. In contrast, interferon-inducible protein-10 (IP-10) and monokine induced by IFN-gamma (Mig) mRNA expression was markedly reduced in mice deficient for IFN-gamma or IFN-gamma receptor, but not in 55 000 MW TNF receptor knockout mice. In situ hybridization experiments demonstrated that IP-10 was highly expressed in lung interstitial macrophages of C57BL/6, but not of IFN-gamma receptor-deficient mice. In contrast to SEB administration, treatment with lipopolysaccharide resulted in a strong induction of IP-10 and Mig in IFN-gamma receptor-deficient mice. Together, these results establish a critical function of IFN-gamma for chemokine induction in acute lung inflammation that is dependent on the nature of the inflammatory stimulus.

Acute Disease↗
PubMed1998

Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis.

Despite considerable progress, peritonitis and sepsis remain life-threatening conditions. To improve the understanding of the pathophysiology encountered in sepsis, a new standardized and highly reproducible murine model of abdominal sepsis termed colon ascendens stent peritonitis (CASP) was developed. In CASP, a stent is inserted into the ascending colon, which generates a septic focus. CASP employing a stent of 14-gauge diameter (14G stent) results in a mortality of 100% within 18 to 48 h after surgery. By inserting stents of small diameters, mortality can be exactly controlled. Thus, CASP surgery with insertion of a 22G or 18G stent (22G or 18G CASP surgery) results in 38 or 68% mortality, respectively. 14G CASP surgery leads to a rapid invasion of bacteria into the peritoneum and the blood. As a consequence, endotoxemia occurs, inflammatory cells are recruited, and a systemic inflammatory response syndrome develops. Interestingly, the most pronounced upregulation of inflammatory cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha] and interleukin-12) is observed in spleen and lungs. CASP surgery followed by stent removal at specific time intervals revealed that all animals survived if intervention was performed after 3 h, whereas removal of the septic focus after 9 h did not prevent death, suggesting induction of autonomous mechanisms of a lethal inflammatory response syndrome. 18G CASP surgery in IFN-gamma receptor-deficient (IFNgammaR-/-) mice revealed an essential role of IFN-gamma in survival of sepsis, whereas TNF receptor p55-deficient (TNFRp55-/-) mice did not show altered survival rates. In summary, this study describes a novel animal model that closely mimics human sepsis and appears to be highly suitable for the study of the pathophysiology of abdominal sepsis. Importantly, this model demonstrates a protective role of IFN-gamma in survival of bacterial sepsis.

Abdomen↗
PubMed1997

Induction of acute inflammatory lung injury by staphylococcal enterotoxin B.

Superantigens stimulate T lymphocytes at high frequency by interacting with appropriate Vbeta segments of the TCR. Challenge of mice with bacterial superantigens such as staphylococcal enterotoxin B (SEB) induces the systemic release of cytokines resulting in septic shock and death of sensitized animals. Analysis of putative pathogenic mechanisms of T cell-dependent septic shock revealed that administration of SEB results in acute inflammatory lung injury characterized by a profound increase in vascular permeability. Injury was associated with marked leukocyte infiltration of the lung and induction of cell adhesion molecules including VCAM-1, ICAM-1, and P-selectin, but not E-selectin. Lung infiltrating leukocytes consisted of granulocytes, mononuclear phagocytes and NK cells with granulocytes representing the major fraction. Consistent with a role of neutrophils as cellular mediators of inflammatory organ injury, we demonstrate activation of circulating granulocytes in mice treated with SEB. When compared with granulocytes of control mice, peripheral blood granulocytes of SEB-treated mice were found to express increased levels of cell surface Mac-1, to down-regulate expression of L-selectin, and to respond with an increased production of toxic oxygen metabolites upon exposure to FMLP. Interestingly, TNF-alpha further enhanced FMLP-induced oxidant production by granulocytes from SEB-treated but not control mice, suggesting that the systemic response to SEB increases granulocyte sensitivity to TNF-alpha-mediated signals. Together, these results suggest that acute inflammatory lung injury may contribute to the pathogenesis of T cell-dependent lethal shock in mice challenged with bacterial superantigens and indicate common pathogenic mechanisms of lung injury induced by a large number of distinct inflammatory stimuli.

Acute Disease↗
PubMed1997

Physical activity and fitness in patients with headache disorders.

Recent studies indicate that aerobic activities might reduce severity and/or frequency of migraine attacks. The present study was intended to investigate whether physical activities and fitness (aerobic endurance, flexibility, and muscle strength endurance) as well as body composition are different in patients with headache disorders and healthy control subjects. The study included 56 patients (aged 17-64 years) with headache disorders (migraine, tension-type, cluster, analgetics abuse, and other types of headache) and 145 age-matched volunteers without history of recurrent or chronic headache. A standardized questionnaire revealed similar self-esteem of physical activities in both groups. Objective physical fitness testing in a representative sample of 22 patients and 36 control subjects showed significantly reduced aerobic endurance in female and male patients as well as reduced flexibility in female patients as compared to control subjects, whereas muscle strength endurance was not significantly different between both groups. Female patients presented with a significantly higher total body fat as compared to control subjects. In conclusion, headache patients turned out to be less physically fit than control subjects. There was a discrepancy between self-esteem and objective test results regarding physical activity and fitness in patients with headache disorders.

Adolescent↗