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Biomedical subjects

M Nielsen

Publications and source records attributed to M Nielsen.

At least 19 recordsLinked to original sources
PubMed2000

Prediction of protein secondary structure at 80% accuracy.

Secondary structure prediction involving up to 800 neural network predictions has been developed, by use of novel methods such as output expansion and a unique balloting procedure. An overall performance of 77.2%-80.2% (77.9%-80.6% mean per-chain) for three-state (helix, strand, coil) prediction was obtained when evaluated on a commonly used set of 126 protein chains. The method uses profiles made by position-specific scoring matrices as input, while at the output level it predicts on three consecutive residues simultaneously. The predictions arise from tenfold, cross validated training and testing of 1032 protein sequences, using a scheme with primary structure neural networks followed by structure filtering neural networks. With respect to blind prediction, this work is preliminary and awaits evaluation by CASP4.

Neural Networks, Computer↗
PubMed2000

Resveratrol reverses tumor-promoter-induced inhibition of gap-junctional intercellular communication.

The naturally occurring stilbene/alexin trans-resveratrol (trans-3,5, 4'-trihydroxystilbene) is a promising agent for the prevention of cancer. We investigated the effect of resveratrol on gap-junctional intercellular communication (GJIC) in WB-F344 rat liver epithelial cells because inhibition of GJIC is an important mechanism of tumor promotion. Seventeen to 50 microM resveratrol increased GJIC significantly by a factor of 1.3 compared with solvent vehicle controls, when the WB-F344 cells were exposed to resveratrol for 6 h. Most tumor promoters, including the phorbol ester TPA and the insecticide DDT, block GJIC. Resveratrol at 17-50 microM also significantly prevented down-regulation of GJIC by TPA and DDT, by a factor of 2.7 and 1.8, respectively. This recovery of GJIC from TPA inhibition was partly correlated with hindered hyperphosphorylation of Cx43. In conclusion, resveratrol was found to enhance GJIC and counteract the effects of tumor promoters on GJIC, and this is likely a mechanism that contributes to the antipromotional and anticarcinogenic properties of resveratrol.

Animals↗
PubMed2000

What and when: parallel and convergent processing in motor control.

Successful motor behavior requires making appropriate response (response selection) at the right time (timing adjustment). Earlier psychological studies have suggested that the response selection and timing adjustment processes are performed serially in separate stages. We tested this hypothesis using functional magnetic resonance imaging. The subjects performed a choice reaction time task in four conditions: two (on-line response selection required or not) by two (on-line timing adjustment required or not). We found that the neural correlates for the two processes were indeed separate: the anterior medial premotor cortex (presupplementary motor area) was selectively active in response selection, whereas the cerebellar posterior lobe was selectively active in timing adjustment. However, the functional separation was only partial in that the lateral premotor cortex and the intraparietal sulcus were active equally for response selection and timing adjustment. The lateral premotor cortex was most active when both processes were required, suggesting that it integrates the information on response selection and the information on timing adjustment; alternatively, it might contribute to the allocation of attentional resources during dual information processing. The intraparietal sulcus was equally active when either response selection or timing adjustment was required, suggesting that it modifies, rather than integrates, these processes. Furthermore, our results suggest that these activations related to response selection and timing adjustment were distinct from sensory or motor processes.

Adult↗
PubMed2000

Acquired generalized lipoatrophy (AGL): highly selective MR lipid imaging and localized (1)H-MRS.

Frequency-selective chemical shift magnetic resonance (MR) imaging was applied on the calf musculature and the abdomen of a patient with acquired generalized lipoatrophy (AGL; Lawrence syndrome), a very rare syndrome affecting selectively several types of adipose tissue accompanied by alterations in glucose and energy metabolism. In addition, (1)H-MRS was used for assessment of intra- (IMCL) and extramyocellular lipid stores (EMCL) in the skeletal musculature of the calf. Results from the AGL patient were compared with an age-matched group of five healthy volunteers. Fat-selective imaging of the calf revealed a total lack of subcutaneous adipose tissue. No EMCL signal was found in the spectra from the soleus muscle of the AGL patient. IMCL signals were present in the spectra but were clearly lower than in the controls (14% of normal value in the soleus muscle). In abdominal images, subcutaneous fat signal was not detectable, as in the calf, but nearly normal conditions were shown for visceral adipose tissue between abdominal organs. Fat-selective images showed the liver with high signal intensity, indicating hepatic steatosis combined with hepatosplenomegaly. Modern chemical shift-selective MR imaging and localized spectroscopy allow a noninvasive and quantitative assessment of tissue composition in patients with disorders of carbohydrate and lipid metabolism.

Adipose Tissue↗
PubMed2000

Interleukin 15 is a growth factor for human thymocytes with preferential effect on CD8(+)cells.

The effects of IL-15, as compared to IL-2, on growth of human thymocytes has been evaluated. Expression of comparable amounts of receptor chains was found on IL-2 and IL-15 cultured thymocytes, as well as comparable receptor signalling. However, IL-15 was superior to IL-2 in promoting CD8(+)thymocyte growth, whereas CD4(+)cells proliferated to a higher extent in IL-2 cultures. CD4(+)8(+)and CD4(-)8(-)thymocytes expanded equally well in both culture types.

CD8-Positive T-Lymphocytes↗
PubMed2000

2-Oxo-2H-Pyrimido[2,1-b]benzothiazoles inhibit brain benzodiazepine receptor binding in vitro.

2-Oxo-2H-pyrimido[2,1-b]benzothiazole derivatives were found to inhibit the in vitro binding of (3)H-Ro 15-1788 ((3)H-flumazenil) to rat cortical benzodiazepine receptors with IC(50) values in the range of 0.7-13 micromol/l. The most potent compound, 2-oxo-4-phenyl-2H-pyrimido[2,1-b]- benzothiazole showed a similar potency to inhibit (3)H-Ro 15-1788 binding to membrane preparations of rat brain cortex, cerebellum and hippocampus as well as to various subunit combinations of recombinant human gamma-aminobutyric acid(A)/benzodiazepine receptors. Scatchard plot analysis showed that 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole is a competitive inhibitor of (3)H-Ro 15-1788 binding to rat brain cortical membrane preparations.

Animals↗
PubMed2000

Ontogeny of oestrogen receptor alpha in gonads and sex ducts of fetal and newborn mice.

The distribution of nuclear oestrogen receptor alpha (ER-alpha) in the sex organs of fetal and newborn mice has been investigated immunohistochemically. There was no visible ER-alpha immunoreaction in the sexually undifferentiated gonads, whereas a faint immunoreaction was detected in a few cells surrounding the sex ducts, the Müllerian and Wolffian ducts. After sex differentiation, the immunoreaction of ER-alpha was observed in various cell types, with the exception of both the male and female germ cells. In the fetal ovary, immunoreaction was restricted to the surface epithelium and a few stroma cells without any preferential localization. In the testis, the number of ER-alpha-immunopositive cells, identified as Leydig and peritubular cells, increased with age. Immediately after sex differentiation, cells surrounding the sex ducts were ER-alpha-immunopositive, but no immunoreaction was detected in the epithelium in either sex. During development, the epithelium of the sex ducts attained a topographic difference in ER-alpha immunoreaction. In females, immunoreaction was detected in the epithelium of the oviduct, but not in the uterus. In males, the immunoreaction of ER-alpha was intense in the epithelium of the efferent ducts, weak in the epididymis and absent in the vas deferens. ER-alpha immunoreaction in the cells surrounding the sex duct differed between the sexes, being high in all these cells in females, but of varying intensity in males. ER-alpha may not play an important role in the development and function of ovarian cells, but may be involved in the development of Leydig and peritubular cells. Furthermore, substances that react with ER-alpha may influence the male germ cells indirectly through the ER-alpha-immunopositive peritubular cells. In addition, in both sexes, ER-alpha-immunopositive cells surrounding the sex ducts may be involved in the mediation of growth and functional differentiation of the ductal epithelium.

Animals↗
PubMed2000

Octylphenol does not mimic diethylstilbestrol-induced oestrogen receptor-alpha expression in the newborn mouse uterine epithelium after prenatal exposure.

This study examined whether the endocrine disruptor octylphenol (OP) mimics the synthetic oestrogen diethylstilbestrol (DES) in ability to induce oestrogen receptor-alpha (ER-alpha) expression in the newborn mouse uterine epithelium after prenatal exposure. Pregnant mice were given daily s.c. injections with DES (10 or 100 microgram DES/kg maternal wt) or OP (100 or 250 mg/kg maternal wt) or with vehicle alone from day 11.5 to 16.5 of pregnancy. ER-alpha expression was evaluated on histological sections by detecting ER-alpha mRNA with the in situ hybridization technique and ER-alpha protein using immunohistochemistry. The immunostaining was quantitated using a microspectrophotometer. Oestrogen-like activity of the DES and OP batches used for in vivo exposure was confirmed in an in vitro assay based on transient gene expression of an oestrogen-dependent reporter plasmid. In mice exposed prenatally to vehicle alone, the uterine epithelium did not express either ER-alpha mRNA or protein, while both were highly expressed in the stroma. Exposure to either DES dose induced the expression of both ER-alpha mRNA and protein in the epithelium, whereas it was unchanged in the stroma. In contrast, neither OP dose induced the expression of ER-alpha mRNA or protein in the epithelium and expression was unchanged in the stroma. Our data stress the importance of in vivo studies when investigating endocrine disruptors.

Animals↗
PubMed2000

Lck is involved in interleukin-2 induced proliferation but not cell survival in human T cells through a MAP kinase-independent pathway.

The role of Lck in IL-2-induced proliferation and cell survival is still controversial. Here, we show that the Src family kinase inhibitor, PP1, reduced the IL-2-induced proliferation of human T cells significantly without inhibiting the anti-apoptotic effect of IL-2. As Lck is the only Src family kinase activated upon IL-2 stimulation in T cells, this indicates that Lck is involved in IL-2-induced proliferation but not survival. IL-2-induced MAP kinase activation was only slightly inhibited by PP1, suggesting that Lck is not essential for IL-2-induced MAP kinase activation in human T cells. We found that an IL-2-sensitive, human mycosis fungoides-derived tumor T cell line is Lck negative, and that the IL-2-induced MAP kinase activation is comparable to non-cancerous T cells, although a little delayed in kinetics. An Lck expressing clone was established by transfecting Lck into mycosis fungoides tumor T cells, but Lck had no influence on the delayed kinetics of MAP kinase activation, indicating that Lck is not essential for MAP kinase activation in mycosis fungoides tumor T cells or in non-cancerous T cells. Taken together, this indicates that Lck is involved in IL-2-induced proliferation, but not cell survival, through a pathway not involving MAP kinase.

Base Sequence↗
PubMed1999

[Good quality of life after heart surgery. Comparable ratings by patients and their relatives].

In a series of 83 patients undergoing coronary artery bypass grafting for angina, perceived QOL (quality of life) was rated by the patients and their spouses, preoperatively and at two and 12 months postoperatively, using the SWED-QUAL instrument. One year after surgery, QOL had improved to a level which might be expected of a normal population comparable in age and gender distribution. Good correlation existed between patient and spouse ratings, especially on physical measures.

Angina Pectoris↗
PubMed1999

Neural representation of a rhythm depends on its interval ratio.

Rhythm is determined solely by the relationship between the time intervals of a series of events. Psychological studies have proposed two types of rhythm representation depending on the interval ratio of the rhythm: metrical and nonmetrical representation for rhythms formed with small integer ratios and noninteger ratios, respectively. We used functional magnetic resonance imaging to test whether there are two neural representations of rhythm depending on the interval ratio. The subjects performed a short-term memory task for a seven-tone rhythm sequence, which was formed with 1:2:4, 1:2:3, or 1:2.5:3.5 ratios. The brain activities during the memory delay period were measured and compared with those during the retention of a control tone sequence, which had constant intertone intervals. The results showed two patterns of brain activations; the left premotor and parietal areas and right cerebellar anterior lobe were active for 1:2:4 and 1:2:3 rhythms, whereas the right prefrontal, premotor, and parietal areas together with the bilateral cerebellar posterior lobe were active for 1:2.5:3.5 rhythm. Analysis on individual subjects revealed that these activation patterns depended on the ratio of the rhythms that were produced by the subjects rather than the ratio of the presented rhythms, suggesting that the observed activations reflected the internal representation of rhythm. These results suggested that there are two neural representations for rhythm depending on the interval ratio, which correspond to metrical and nonmetrical representations.

Adult↗
PubMed1999

Structure-activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABA(A) receptor complex.

The affinities for the benzodiazepine binding site of the GABA(A) receptor of 21 flavonoids have been studied using [(3)H]flumazenil binding to rat cortical membranes in vitro. We show that flavonoids with high affinity for the benzodiazepine receptor in vitro spanning the whole efficacy range from agonists (1q) to inverse agonists (1l) can be synthesized. The receptor binding properties of the flavonoids studied can successfully be rationalized in terms of a comprehensive pharmacophore model recently developed by Cook and co-workers (Drug Des. Dev. 1995, 12, 193-248), supporting the validity of this model. However, in contrast to the requirement by the model that an interaction with the hydrogen bond-accepting site A2 is necessary for compounds to display inverse agonistic activity, 6-methyl-3'-nitroflavone (1l), which cannot engage in such an interaction, nevertheless displays inverse agonism. The analysis of the binding affinities of 3'- and 4'-substituted flavones in terms of the pharmacophore model has yielded new information for the further development of the pharmacophore model.

Animals↗
PubMed1999

Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3.

Signal transducers and activators of transcription (STATs) are rapidly phosphorylated on tyrosine residues in response to cytokine and growth factor stimulation of cell surface receptors. STATs hereafter are translocated to the nucleus where they act as transcription factors. Recent reports suggest that serine phosphorylation of STATs also is involved in the regulation of STAT-mediated gene transcription. Here, we studied the role of serine/threonine phosphatases in STAT3 signaling in human antigen-specific CD4(+) T cell lines and cutaneous T cell lymphoma lines, expressing a constitutively activated STAT3. We show that an inhibitor of protein phosphatases (PPs) PP1/PP2A, calyculin A, induces (i) phosphorylation of STAT3 on serine and threonine residues, (ii) inhibition of STAT3 tyrosine phosphorylation and DNA binding activity, and (iii) relocation of STAT3 from the nucleus to the cytoplasm. Similar results were obtained with other PP2A inhibitors (okadaic acid, endothall thioanhydride) but not with inhibitors of PP1 (tautomycin) or PP2B (cyclosporine A). Pretreatment with the broad serine/threonine kinase inhibitor staurosporine partly blocked the calyculin A-induced STAT3 phosphorylation, whereas inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase-1 extracellular-regulated kinase-kinase, mitogen-activated protein p38 kinase, and phosphatidylinositol 3-kinase, did not. In conclusion, we provide evidence that PP2A plays a crucial role in the regulation of STAT3 phosphorylation and subcellular distribution in T cells. Moreover, our findings suggest that the level of STAT3 phosphorylation is balanced between a staurosporine-sensitive kinase(s) and PP2A.

CD4-Positive T-Lymphocytes↗
PubMed1999

Cutting edge: TCR stimulation by antibody and bacterial superantigen induces Stat3 activation in human T cells.

Recent data show that TCR/CD3 stimulation induces activation of Stat5 in murine T cells. Here, we show that CD3 ligation by mAb and Staphylococcal enterotoxin (SE) induce a rapid, gradually accumulating, long-lasting tyrosine, and serine phosphorylation of Stat3 (but not Stat5) in allogen-specific human CD4+ T cell lines. In contrast, IL-2 induces a rapid and transient tyrosine and serine phosphorylation of Stat3. Compared with IL-2, CD3 ligation induces a delayed Stat3 binding to oligonucleotide probes from the ICAM-1 and IL-2R alpha promoter. CD3-mediated activation of Stat3 is almost completely inhibited by a Src kinase inhibitor (PP1), whereas IL-2-induced Stat3 activation is unaffected. In conclusion, we show that CD3 ligation by mAb and SE triggers a rapid, PP1-sensitive tyrosine and serine phosphorylation of Stat3 in human CD4+ T cells. Moreover, we provide evidence that TCR/CD3 and IL-2 induce Stat3 activation via distinct signaling pathways.

Antibodies, Monoclonal↗
PubMed1999

Effects of isoflurane and hexafluorodiethyl ether on human recombinant GABA(A) receptors expressed in Sf9 cells.

Effects of volatile anesthetics and a volatile convulsant on human recombinant gamma-aminobutyric acid (GABA) type A receptor responses were studied using the whole cell configuration of the patch clamp technique. Sf9 cells were transfected with bacuroviruses carrying cDNAs of alpha1beta2, alpha1beta2gamma2s, alpha3beta2 and alpha3beta2gamma2s subunit combinations of the human GABA(A) receptor. Clinical concentrations of isoflurane (a volatile anesthetic) enhanced the GABA-induced current of the alpha1beta2gamma2s and alpha3beta2gamma2s GABA(A) subunit combinations. On the other hand, isoflurane suppressed the current of the alpha1beta2 and alpha3beta2 subunit combinations, indicating that the anesthetic effects depended upon the presence of gamma2s subunit. A high concentration (2 mM) of isoflurane generated a surge current following the washout of GABA and the anesthetic. Hexafluorodiethyl ether (a volatile convulsant) decreased the GABA-response of the both alpha3beta2gamma2s and alpha3beta2 constructs without generating a surge current. The results suggest that volatile agents affect the receptor-ionophore complex via direct interaction with proteins but not through a perturbation of the membrane lipid environment. A hypothetical sequential model for the anesthetic action is presented.

Anesthetics, Inhalation↗
PubMed1999

Arginine residue 120 of the human GABAA receptor alpha 1, subunit is essential for GABA binding and chloride ion current gating.

The effect of mutating the conserved amino acid residue arginine 120 to lysine in the GABAA receptor alpha 1 subunit was studied. In electrophysiological experiments, the arginine 120 lysine (R120K) mutation in the alpha 1 subunit, when co-expressed with beta 2 and gamma 2 subunits in Sf-9 insect cells, induces a 180-fold rightward shift of the GABA dose-response curve compared with wild type alpha 1 beta 2 gamma 2s GABAA receptors. The diazepam potentiation of GABA-gated chloride ion currents was not affected. The binding of the GABAA ligands [3H]muscimol and [3H]SR 95531 to alpha 1 (R120K) beta 2 gamma 2s GABAA receptors was abolished but the binding affinity of the benzodiazepine receptor ligand [3H]flunitrazepam was unchanged. These results suggest that the arginine residue 120 in the alpha 1 subtype of the GABAA receptor is essential for GABA binding.

Amino Acid Sequence↗