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  • 101. Högstrand, K
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute / Stockholm University.
    Gene conversion of major histocompatibility complex genes in the mouse spermatogenesis is a premeiotic event1997In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 8, no 12, p. 2511-2517Article in journal (Refereed)
    Abstract [en]

    The molecular genetic mechanism of gene conversion in higher eukaryotes remains unknown. We find it of considerable interest to determine when during spermatogenesis gene conversion occurs. We have therefore purified pachytene spermatocytes and haploid spermatocytes from adult mice and analyzed these fractions for the presence of gene conversion products resulting from the transfer between the major histocompatibility complex class II genes Ebd and Abk in a polymerase chain reaction assay. We have further isolated spermatogenic cells from prepubescent mice and analyzed them for the presence of the same gene conversion products. We can detect gene conversion products in testis cells as early as in 8-d-old mice where the only existing spermatogenic cells are spermatogonia. The frequency of gene conversion products remains the same as the cells reach meiosis in 18-d-old mice, and is unchanged after meiosis is completed in haploid spermatocytes. Gene conversion of this specific fragment therefore appears to be a premeiotic event and, consequently, relies on genetic mechanisms other than normal meiotic recombination.

  • 102. Högstrand, K.
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Gene conversion of major histocompatibility complex genes is associated with CpG-rich regions1999In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 49, no 5, p. 446-455Article in journal (Refereed)
    Abstract [en]

    We examined 32 DNA sequences of mouse and human major histocompatibility complex (MHC) genes believed to have been subjected to gene conversion events. All regions of the mouse H2 genes as well as the human HLA genes which have been implied to be involved in gene conversion events had elevated levels of CpG dinucleotides, whereas the rest of the genes showed extensive CpG suppression. Mouse MHC genes which have been suspected but not directly implied to be involved in gene conversion events also showed elevated levels of CpG dinucleotides. Moreover, both mouse and human MHC genes which have never been suspected of undergoing gene conversion had low levels of CpG throughout the genes. These results indicate that high CpG levels are correlated with gene conversion rather than with polymorphism, as non-polymorphic genes that have been implicated as gene conversion donors also have elevated levels of CpG dimers in the involved regions whereas polymorphic genes which have never been considered to undergo gene conversion events have a low level of CpG dinucleotides. We also studied the methylation pattern of CpG dimers in the Abk gene by restriction enzyme digestion of mouse testis DNA followed by Southern blot and hybridization to an Abk-specific probe. The examined CpG dimers in prepubescent mice, where the latest germline stages are spermatogonia, leptene, or pachytene, are respectively non-methylated. Accordingly, the CpG dimers appear to be non-methylated in germline DNA from the testis of prepubescent mice, where gene conversions have been reported to occur.

  • 103.
    Imreh, Gabriela
    Södertörn University, Avdelning Naturvetenskap. Stockholms universitet.
    Distribution and dynamics of a nuclear pore membrane protein2002Doctoral thesis, comprehensive summary (Other academic)
  • 104.
    Imreh, Gabriela
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholms unviersitet.
    de Monvel, J. B
    Karolinska universitetssjukhuset.
    Branden, L.
    Karolinska institutet.
    Hallberg, Einar
    Södertörn University, Avdelning Naturvetenskap.
    ER retention may play a role in sorting of the nuclear pore membrane Protein POM121 towards the NPCManuscript (preprint) (Other academic)
  • 105.
    Imreh, Gabriela
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Hallberg, Einar
    Södertörn University, Avdelning Naturvetenskap.
    An integral membrane protein from the nuclear pore complex is also present in the annulate lamellae: Implications for annulate lamella formation2000In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 259, no 1, p. 180-190Article in journal (Refereed)
    Abstract [en]

    Annulate lamellae (AL) are cytoplasmic arrays of stacked membrane cisternae containing densely packed pore complexes which are similar in structure to the nuclear pore complexes (NPCs) and thus referred to as annulate lamella pore complexes (ALPCs). We have recently shown that the integral nuclear pore membrane protein POM121 tagged with green fluorescent protein was correctly targeted to the nuclear pores (H. Soderqvist et al., 1997, fur. J. Biochem. 250, 808-813). Here we have investigated if POM121 fused to three tandem molecules of yellow fluorescent protein YFP) (POM121-YFP3,) also was able to distribute in the extensive and well-characterized Al; of RC37 and BMGE cells. Transfected RC37 or BMGE cells displayed YFP fluorescence around the nuclear envelope, as well. as in the cytoplasmic AL structures. The YFP fluorescence colocalized perfectly with immunostaining using antibodies specific for different NPC proteins. The AL of both transfected and untransfected BMGE cells resisted extractions with Tx-100 and 250 mM NaCl, but were completely solubilized at 450 mM NaCl. Loss of YFP fluorescence and immunostaining for other NPC proteins correlated under all extraction conditions tested, suggesting that overexpressed POM121-YFP3, had become an integrated part both of the NPCs and of the ALPCs. Furthermore, we have generated a stable BHK cell line expressing POM121YFP(3,) located exclusively at the nuclear pores. Treatment with vinblastine sulfate, which induces formation of Al; in a variety of cells, resulted in distribution of POM121-YFP3, into cytoplasmic foci colocalizing with immunostaining for peripheral NPC proteins. Taken together, the results show that YFP-tagged POM121 is able to distribute in drug-induced or naturally occurring AL, suggesting that POM121 is a natural constituent of ALPCs. In COS cells, which normally lack or have very little AT-I, YFP-tagged POM121 distributed in the nuclear pores when expressed at low levels. However, at high expression levels the YFP fluorescence also distributed in a number of brightly fluorescing cytoplasmic dots or foci, which were not present in untransfected cells. This was also true for untagged POM121. The cytoplasmic foci varied in size from 0.1 to 2 mu m and were distinctly located in the immediate vicinity of ER cisternae (without colocalizing) and also contained other nuclear pore proteins, indicating that they may represent cytoplasmic AL. This idea is supported by time-lapse studies of postmitotic assembly of these structures. This raises the question of the role of POM121 in ALPC and NPC biogenesis.

  • 106.
    Imreh, Gabriela
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Maksel, Danuta
    Södertörn University, Avdelning Naturvetenskap.
    de Monvel, J B
    Branden, L
    Hallberg, Einar
    Södertörn University, Avdelning Naturvetenskap.
    ER retention may play a role in sorting of the nuclear pore membrane protein POM1212003In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 284, no 2, p. 173-184Article in journal (Refereed)
    Abstract [en]

    Integral membrane proteins of the nuclear envelope (NE) are synthesized on the rough endoplasmic reticulum (ER) and following free diffusion in the continuous ER/NE membrane system are targeted to their proper destinations due to interactions of specific domains with other components of the NE. By studying the intracellular distribution and dynamics of a deletion mutant of an integral membrane protein of the nuclear pores, POM121, which lacks the pore-targeting domain, we investigated if ER retention plays a role in sorting of integral membrane proteins to the nuclear envelope. A nascent membrane protein lacking sorting determinants is believed to diffuse laterally in the continuous ER/NE lipid bilayer and expected to follow vesicular traffic to the plasma membrane. The GFP-tagged deletion mutant, POM121(1-129)-GFP, specifically distributed within the ER membrane, but was completely absent from the Golgi compartment and the plasma membrane. Experiments using fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP) demonstrated that despite having very high mobility within the whole ER network (D = 0.41 +/- 0.11 mum(2)/s) POM121(1-129)-GFP was unable to exit the ER. It was also not detected in post-ER compartments of cells incubated at 15degreesC. Taken together, these experiments show that amino acids 1-129 of POM121 are able to retain GFP in the ER membrane and suggest that this retention occurs by a direct mechanism rather than by a retrieval mechanism. Our data suggest that ER retention might be important for sorting of POM121 to the nuclear pores.

  • 107. Janosik, T
    et al.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Oxidative coupling of indoline-2-thione or oxindole: Formation of cyclic and acyclic indole trimers2002In: Heterocycles, ISSN 0385-5414, E-ISSN 1881-0942, Vol. 57, no 7, p. 1273-1278Article in journal (Refereed)
    Abstract [en]

    Oxidation of indoline-2-thione using p-toluenesulfonyl azide produced a modest yield of the structurally novel cyclic sulfur containing indole trimer (12). In contrast, the oxidation of oxindole with iodine instead produced an acyclic trimeric indole derivative.

  • 108.
    Janosik, Tomasz
    et al.
    Dartmouth College, Hanover, United States .
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Five-membered ring systems: Pyrroles and benzo derivatives2003In: Progress in Heterocyclic Chemistry, ISSN 0959-6380, Vol. 15, no C, p. 140-166Article in journal (Refereed)
  • 109.
    Janosik, Tomasz
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Romero, Ivan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Stensland, B
    Stålhandske, C
    Marques, M M B
    Santos, M M M
    Lobo, A M
    Prabhakar, S
    Duarte, M F
    Florencio, M H
    Synthetic, spectroscopic, and X-ray crystallographic studies of [1,2,7,8]tetrathiacyclododecino[4,3-b: 5,6-b': 10,9-b": 11,12-b''']tetraindoles2002In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 8, p. 1392-1396Article in journal (Refereed)
    Abstract [en]

    Two conformationally different [1,2,7,8]tetrathiacyclododecino[4,3-b:5,6-b':10,9-b":11,12-b''']tetraind oles 9a and 9b have been isolated in good yields, and the existence of a third conformer 9c in solution was demonstrated by mass spectrometry and H-1 NMR spectroscopy. The interconversions of the tetraindoles 9a-c have also been studied. The conformation of 9b was confirmed by X-ray crystallography, while the conformations of 9a and 9b were assigned on the basis of spectroscopic data, and were also supported by molecular modelling studies. In addition, the elusive dithiin 3 was isolated and the structure was proven by X-ray crystallography.

  • 110.
    Janosik, Tomasz
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Johnson, Ann-Louise
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Synthesis of the marine alkaloids rhopaladins A, B, C and D2002In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 58, no 14, p. 2813-2819Article in journal (Refereed)
    Abstract [en]

    The total synthesis of all four known rhopaladins, A-D, isolated from the Okinawan marine tunicate Rhopalaea sp., in two synthetic steps is described, involving an imidate based cyclization with tryptophan esters as the key step to afford the appropriately substituted imidazolinone unit. A short and efficient new synthesis of indol-3-yl-carbonyl nitriles from indol-3-yl-carboxaldehydes and trimethylsilyl cyanide, followed by oxidation with DDQ is also described.

  • 111.
    Janosik, Tomasz
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Stensland, B
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Sulfur-rich heterocycles from 2-metalated benzo[b]thiophene and benzo[b]furan: Synthesis and structure2002In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 67, no 17, p. 6220-6223Article in journal (Refereed)
    Abstract [en]

    The reaction of 2-lithiated benzo[b]thiophene with 8 equiv of elemental sulfur was found to give pentathiepino[6,7-b]benzo[d]thiophene. In contrast, treatment of 2-lithiated benzo[b]furan with sulfur under similar conditions produced the interesting ring system bis(benzo[4,5]-furo)[2,3-e:3',2'-g][1,2,3,4]tetrathiocine. Both of these new cyclic polysulfides were studied by X-ray crystallography. Two polymorphic forms of pentathiepino[6,7-b]benzo[d]thiophene were found, displaying similar conformations but different packing schemes, which was also evident from powder diffraction data.

  • 112.
    Jernberg, Cecilia
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Jansson, Janet K
    Södertörn University, Avdelning Naturvetenskap.
    Impact of 4-chlorophenol contamination and/or inoculation with the 4-chlorophenol-degrading strain, Arthrobacter chlorophenolicus A6L, on soil bacterial community structure2002In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 42, no 3, p. 387-97Article in journal (Refereed)
    Abstract [en]

    The 4-chlorophenol-degrading strain, Arthrobacter chlorophenolicus A6L (chromosomally tagged with the firefly luciferase gene, luc) was inoculated into 4-chlorophenol-contaminated soil to assess the impact of bioaugmentation with a biodegrading strain on the indigenous microbiota. Simultaneously, the impact of 4-chlorophenol alone, or inoculation with A. chlorophenolicus into non-contaminated soil, was addressed. Using terminal restriction fragment length polymorphism (T-RFLP) several significant changes were detected in community fingerprint patterns obtained from soil microcosms treated under the different conditions. The relative abundances of some populations, as judged by the relative intensity of terminal restriction fragments, were significantly impacted by either 4-chlorophenol, A. chlorophenolicus inoculation, or by a combination of both inoculation and 4-chlorophenol contamination. Some populations were significantly stimulated and others were significantly repressed when compared to control soil with no additions. For several peaks, the positive or negative impact imposed by the treatments increased over the 13-day incubation period. Some members of the bacterial community were specifically sensitive to A. chlorophenolicus inoculation or to 4-chlorophenol contamination, whereas other populations remained relatively unaffected by any of the treatments. The A. chlorophenolicus inoculum was also monitored by T-RFLP and was found to have a significantly higher relative abundance in soil contaminated with 4-chlorophenol. These results were substantiated by a high correlation to luciferase activity measurements and the number of colony forming units of the inoculum. Therefore, the A. chlorophenolicus A6L population was positively stimulated by the presence of the 4-chlorophenol substrate (180 microg g(-1) soil) that it catabolized during the first 8 days of the incubation period as a carbon and energy source. Together, these results demonstrate that specific populations in the soil bacterial community rapidly fluctuated in response to specific disturbances and the resulting shifts in the community may therefore represent an adjustment in community structure favoring those populations best capable of responding to novel stress scenarios.

  • 113. Jimenez, A
    et al.
    Johansson, C
    Ljung, J
    Sagemark, Johan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Berndt, Kurt D
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Ren, B
    Tibbelin, G
    Ladenstein, R
    Kieselbach, T
    Holmgren, A
    Gustafsson, J A
    Miranda-Vizuete, A
    Human spermatid-specific thioredoxin-1 (Sptrx-1) is a two-domain protein with oxidizing activity2002In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 530, no 1-3, p. 79-84Article in journal (Refereed)
    Abstract [en]

    Spermatid-specific thioredoxin-1 (Sptrx-1) is the first member of the thioredoxin family of proteins with a tissue-specific expression pattern, found exclusively in the tail of elongating spermatids and spermatozoa. We describe here further biochemical characterization of human Sptrx-1 protein structure and enzymatic activity. In gel filtration chromatography human Sptrx-1 eluates as a 400 kDa protein consistent with either an oligomeric form, not maintained by intermolecular disulfide bonding, and/or a highly asymmetrical structure. Analysis of circular dichroism spectra of fragments 1-360 and 361-469 and comparison to spectra of full-length Sptrx-1 supports a two-domain organization with a largely unstructured N-terminal domain and a folded thioredoxin-like C-terminal domain. Functionally, Sptrx-1 behaves as an oxidant in vitro when using selenite, but not oxidized glutathione, as electron acceptor. This oxidizing enzymatic activity suggests that Sptrx-1 might govern the stabilization (by disulfide cross-linking) of the different structures in the developing tail of spermatids and spermatozoa.

  • 114.
    Johansson, Karin
    Södertörn University, Avdelning Naturvetenskap.
    Squatting i Alexandra: Om illegal bosättning i Sydafrika och hur landets bostadspolitik påverkats av Habitat II2000Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Squatting innebär att människor illegalt bosätter sig på mark eller ockuperar tomma hus för att ha någonstans att bo. I samband med att världens storstäder växer, växer även squattingområden. För att förbättra situationen för bland annat squatters, hölls 1996 en FN-konferens, Habitat II.

    Syftet med uppsatsen är att belysa problemet med squatting och undersöker om Habitat II:s beslut haft någon inverkan på det deltagande landet Sydafrika. Den teoretiska ansatsen är realism och managerialism, där man menar att bostadssegregation beror på sociala och rumsliga hinder, samt att det är de med makt som ansvarar för bostadsituationen. De dokument från Habitat II har studerats som berör squatters samt sydafrikanska bostadspolitiska dokument. Även en litterär fallstudie av förstaden Alexandra har gjorts.

    Squatting i Sydafrika till stor del beror på den tidigare apartheid som bedrevs i landet under större delen av 1900-talet. Squatters situation har i viss mån förbättrats efter 1996, men mer beroende på apartheids avvecklande och de nya regeringarnas vilja att förändra situationen än Habitat II:s dokument. Habitat II poängterar hur viktigt det är med lokalt deltagande organisationer och dessa har stor roll i förbättrandet för squatters. Många organisationer i Sydafrika har drivit bostadsfrågan framåt lokalt. Samtidigt är flera organisationer alltför korrupta, likaså de bygg- och finansieringsbolag som ska ordna bostäder, varför situationen för många squatters fortfarande är oförändrad.

  • 115.
    Johansson, Magnus
    Södertörn University College, Avdelning Naturvetenskap.
    Flavivirus: ett växande globalt hälsoproblem2003In: Teknik & vetenskap, ISSN 1402-5701, Vol. 19, no 1, p. -46Article in journal (Other (popular science, discussion, etc.))
  • 116. Johnson, A L
    et al.
    Janosik, T
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap.
    Synthesis of the diketopiperazine dipodazine2002In: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, p. 57-61Article in journal (Refereed)
    Abstract [en]

    The diketopiperazine derivative dipodazine (1), isolated from Penicillium dipodomyis, has been synthesized via a stereoselective aldol condensation from N-protected indole-3-carboxaldehyde and 1,4-diacetyl-2,5-piperazinedione (3) in the presence of cesium carbonate.

  • 117. Jouve, Karine
    et al.
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Oxidative cyclization of N-methyl- and N-benzoylpyridylthioureas. Preparation of new thiazolo[4,5-b] and [5,4-b]pyridine derivatives2003In: Journal of Heterocyclic Chemistry, ISSN 0022-152X, E-ISSN 1943-5193, Vol. 40, no 2, p. 261-268Article in journal (Refereed)
  • 118. Juntti-Berggren, L
    et al.
    Webb, D L
    Arkhammar, P O G
    Schultz, V
    Schweda, Elke K H
    Södertörn University, Avdelning Naturvetenskap.
    Tornheim, K
    Berggren, P O
    Dihydroxyacetone-induced oscillations in cytoplasmic free Ca2+ and the ATP/ADP ratio in pancreatic beta-cells at substimulatory glucose2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 42, p. 40710-40716Article in journal (Refereed)
    Abstract [en]

    Glucose stimulation of pancreatic beta-cells causes oscillatory influx of Ca2+, leading to pulsatile insulin secretion. We have proposed that this is due to oscillations of glycolysis and the ATP/ADP ratio, which modulate the activity of ATP-sensitive K+ channels. We show here that dihydroxyacetone, a secretagogue that feeds into glycolysis below the putative oscillator phosphofructokinase, could cause a single initial peak in cytoplasmic free Ca2+ ([Ca2+](i)) but did not by itself cause repeated oscillations in [Ca2+](i) in mouse pancreatic beta-cells. However, in the presence of a substimulatory concentration of glucose (4 mM), dihydroxyacetone induced [Ca2+](i) oscillations. Furthermore, these oscillations correlated with oscillations in the ATP/ADP ratio, as seen previously with glucose stimulation. Insulin secretion in response to dihydroxyacetone was transient in the absence of glucose but was considerably enhanced and somewhat prolonged in the presence of a substimulatory concentration of glucose, in accordance with the enhanced [Ca2+](i) response. These results are consistent with the hypothesized role of phosphofructokinase as the generator of the oscillations. Dihydroxyacetone may affect phosphofructokinase by raising the free concentration of fructose 1,6-bisphosphate to a critical level at which it activates the enzyme autocatalytically, thereby inducing the pulses of phosphofructokinase activity that cause the metabolic oscillations.

  • 119.
    Kieselbach, T
    et al.
    Karolinska Institutet.
    Bystedt, Maria
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Hynds, P
    University of Warwick, UK.
    Robinson, C
    University of Warwick, UK.
    Schröder, Wolfgang P
    Södertörn University, Avdelning Naturvetenskap.
    A peroxidase homologue and novel plastocyanin located by proteomics to the Arabidopsis chloroplast thylakoid lumen2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 480, no 2-3, p. 271-276Article in journal (Refereed)
    Abstract [en]

    A study by two-dimensional electrophoresis showed that the soluble, lumenal fraction of Arabidopsis thaliana thylakoids can be resolved into 300 protein spots. After subtraction of low-intensity spots and accounting for low-level stromal contamination, the number of more abundant, lumenal proteins was estimated to be between 30 and 60. Two of these proteins have been identified: a novel plastocyanin that also was the predominant component of the total plastocyanin pool, and a putative ascorbate peroxidase. Import studies shamed that these proteins are routed to the thylakoid lumen by the Sec- and delta pH-dependent translocation pathways, respectively, In addition, novel isoforms of PsbO and PsbQ were identified.

  • 120.
    Kihlmark, Madeleine
    Södertörn University, Avdelning Naturvetenskap. Stockholms universitet.
    Targeting of a nascent integral membrane protein to the nuclear pores and its degradation during apoptosis2002Doctoral thesis, comprehensive summary (Other academic)
  • 121.
    Kihlmark, Madeleine
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Imreh, Gabriela
    Södertörn University, Avdelning Naturvetenskap.
    Hallberg, Einar
    Södertörn University, Avdelning Naturvetenskap.
    Sequential degradation of proteins from the nuclear envelope during apoptosis2001In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 114, no 20, p. 3643-3653Article in journal (Refereed)
    Abstract [en]

    We have produced new antibodies specific for the integral pore membrane protein POM121. Using these antibodies we show that during apoptosis POM121 becomes proteolytically degraded in a caspase-dependent manner. The POM121 antibodies and antibodies specific for other proteins of the nuclear envelope were used in a comparative study of nuclear apoptosis in staurosporine-treated buffalo rat liver cells. Nuclei from these cells were classified in three different stages of apoptotic progression: stage I, moderately condensed chromatin surrounded by a smooth nuclear periphery; stage II, compact patches of condensed chromatin collapsing against a smooth nuclear periphery; stage III, round compact chromatin bodies surrounded by grape-shaped nuclear periphery. We have performed double labeling immunofluorescence microscopy of individual apoptotic cells and quantitative immunoblotting analysis of total proteins from apoptotic cell cultures. The results showed that degradation of nuclear envelope marker proteins occurred in a specific order. POM121 degradation occurred surprisingly early and was initiated before nucleosomal DNA degradation could be detected using TUNEL assay and completed before clustering of the nuclear pores. POM121 was eliminated significantly more rapid compared with NUP153 (a peripheral protein located in the nucleoplasmic basket of the nuclear pore complex) and lamin B (a component of the nuclear lamina). Disappearance of NUP153 and lamin B was coincident with onset of DNA fragmentation and clustering of nuclear pores. By contrast, the peripheral NPC protein p62 was degraded much later. The results suggest that degradation of POM121 may be an important early step in propagation of nuclear apoptosis.

  • 122.
    Kihlmark, Madeleine
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholms unviersitet.
    Rustum, Cecilia
    Södertörn University, Avdelning Naturvetenskap. Stockholms universitet.
    Eriksson, Charlotta
    Södertörn University, Avdelning Naturvetenskap. Karolinska institutet.
    Beckman, M
    Stockholms universitet.
    Iverfeldt, Kerstin
    Stockholms universitet.
    Hallberg, Einar
    Södertörn University, Avdelning Naturvetenskap.
    Caspase-3 dependent cleavage of POM121 in relation to nuclear apoptosisManuscript (preprint) (Other academic)
  • 123.
    Kniola, Barbara
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    O'Toole, E
    McIntosh, J R
    Mellone, B
    Allshire, R
    Mengarelli, S
    Hultenby, K
    Ekwall, Karl
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    The domain structure of centromeres is conserved from fission yeast to humans2001In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 12, no 9, p. 2767-2775Article in journal (Refereed)
    Abstract [en]

    The centromeric DNA of fission yeast is arranged with a central core flanked by repeated sequences. The centromere-associated proteins, Mis6p and Cnp1p (SpCENP-A), associate exclusively with central core DNA, whereas the Swi6 protein binds the surrounding repeats. Here, electron microscopy and immunofluorescence light microscopy reveal that the central core and flanking regions occupy distinct positions within a heterochromatic domain. An "anchor" structure containing the Ndc80 protein resides between this heterochromatic domain and the spindle pole body. The organization of centromere-associated proteins in fission yeast is reminiscent of the multilayered structures of human kinetochores, indicating that such domain structure is conserved in eukaryotes.

  • 124.
    Koeck, Philip J B
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Quantization errors in averaged digitized data2001In: Signal Processing, ISSN 0165-1684, E-ISSN 1872-7557, Vol. 81, no 2, p. 345-356Article in journal (Refereed)
    Abstract [en]

    Analytic expressions which describe average quantization errors in digitized data with additive noise are derived. The magnitude of this error depends on the noise present in the analog signal, the bin-size (the difference between neighboring quantization levels) and also the signal itself. An iterative process, which corrects for these residual quantization errors after averaging, is proposed and tested in simulations. Alternatively a method for avoiding quantization errors during digitization of signals which will later be averaged is suggested.

  • 125. Kumblad, Linda
    et al.
    Gilek, Michael
    Södertörn University, Avdelning Naturvetenskap.
    Naeslund, Björn
    Kautsky, Ulrik
    An ecosystem model of the environmental transport and fate of carbon-14 in a bay of the Baltic Sea, Sweden2003In: Ecological Modelling, ISSN 0304-3800, E-ISSN 1872-7026, Vol. 166, no 3, p. 193-210Article in journal (Refereed)
    Abstract [en]

    The environmental transport and fate of a hypothetical discharge of radioactive C-14 from the Swedish final repository for radioactive operational waste (SFR) was investigated using an ecosystem modelling approach. It involved identification, quantification and dynamic modelling of the main flows and storages of carbon both in the physical environment and in the food web of a bay in the Baltic Sea. In the model, C-14 was introduced into the food web via photosynthesising organisms. Contamination of the modelled ecosystem was assessed assuming a release of 51.3 MBq per year for 1000 years. The implications of changes of two parameters on the C-14 fate were examined: route of C-14 entry in the food web and water exchange. Modelling results were also used to estimate steady-state C-14-concentrations in biota, to investigate the time needed to reach steady-state and to calculate the ecological half-life of the radionuclide for the modelled compartments and the ecosystem. Since the modelled area is characterised by a fast water exchange, most of the discharged C-14 was flushed out of the system (99.8%), and diluted in a much larger recipient. However, a small fraction of the discharge was assimilated by primary producers, which enabled subsequent transfer of C-14 to organisms at higher trophic levels (e.g. fish, seals and humans). In general, the highest C-14-concentrations were observed in benthic plants and benthic macrograzers followed by fish and other organisms. An assumption of C-14 entry into the food web via benthic primary producers was found to lead to increased concentrations in-biota (especially benthic organisms) and reduced rates of water exchange were also observed to significantly increase the C-14 exposure of the organisms.

  • 126. Landberg, Katarina
    et al.
    Nilsson, Lars
    Para, Alessia
    Uppsala universitet, Fysiologisk botanik.
    Sundås Larsson, Annika
    Södertörn University, Avdelning Naturvetenskap.
    The TERMINAL FLOWER2 (TFL2) Gene Regulates the Transition to Flowering by Repressing Gene ActivityManuscript (preprint) (Other academic)
  • 127. Langefors, Åsa
    et al.
    Lohm, Jakob
    Grahn, Mats
    Södertörn University College, Avdelning Naturvetenskap.
    Andersen, Øivind
    von Schantz, Torbjörn
    Association between major histocompatibility complex class IIB alleles and resistance to Aeromonas salmonicida in Atlantic salmon2001In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 268, no 1466, p. 479-485Article in journal (Refereed)
    Abstract [en]

    We have tested the importance of genetic variation in the major histocompatibility complex (MHC) class IIB in Atlantic salmon (Salmo salar) for survival after challenge with a highly virulent bacterial pathogen. Forty juvenile full siblings from each of 120 families were infected with the bacterium Aeromonas salmonicida, which causes high mortality in salmon due to furunculosis. Fishes from high-resistance (HR, < 35% mortality) and low-resistance (LR, > 80% mortality) families were screened for their MHC class IIB genotypes using the denaturing gradient gel electrophoresis (DGGE) technique. The exon 2 sequences, encoding the major part of the peptide-binding region, were established far each DGGE fragment. One allele, e, containing a missense single base substitution was significantly more prevalent in HR families than in LR families. An odds-ratio test showed that broods carrying this allele had a 12-fold higher chance of being HR than broods without the e allele. A second allele, i, showed significantly higher frequencies in uninfected and surviving individuals than in infected dead individuals. A third allele, j, tended to be more prevalent both in LR families and in individuals that had died of the infection. There was no correlation between MHC heterozygosity and resistance to A. salmonicida. Our results support the hypothesis that MHC polymorphism is maintained through pathogen-driven selection acting by means of frequency-dependent selection rather than heterozygous advantage.

  • 128. Langefors, Åsa
    et al.
    Lohm, Jakob
    von Schantz, Torbjörn
    Grahn, Mats
    Södertörn University College, Avdelning Naturvetenskap.
    Screening of Mhc variation in Atlantic salmon (Salmo salar): a comparison of restriction fragment length polymorphism (RFLP), denaturing gradient gel electrophoresis (DGGE) and sequencing2000In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 9, no 2, p. 215-219Article in journal (Refereed)
    Abstract [en]

    We compared three different molecular methods currently used for screening of Mhc variation in population studies of Atlantic salmon. Restriction fragment length polymorphism (RFLP) of the entire class II gene detected 22 haplotypes. Seventeen exon 2 sequences were obtained from individuals carrying the 22 haplotypes, two of which had not been detected by RFLP. The six alleles (27%) detected by RFLP and not by exon 2 sequencing probably resulted from sequence variation outside exon 2. Within exon 2, RFLP differentiated 88% of the sequences. Alternatively, denaturing gradient gel electrophoresis (DGGE) performed under two run conditions detected 94% of the sequence variation. Both RFLP using different probes, and the two PCR-based methods using three different primer pairs, suggest that there is only a single Mhc class II B gene in the Baltic populations of Atlantic salmon.

  • 129. Larsson, Carl-Magnus
    et al.
    Brewitz, Erica
    Jones, Celia
    Avila, R.
    Beresford, Nick
    Brown, Justin
    Fortin, C.
    Garnier-Laplace, Jacqueline
    Gilek, Michael
    Södertörn University College, Avdelning Naturvetenskap.
    Oughton, Deborah
    Pentreath, J.
    Pröhl, Gerhard
    Sundell-Bergman, S.
    Zinger-Gize, Irène
    Formulating the FASSET assessmentcontext: FASSET deliverable 2: part 12002Report (Other academic)
  • 130. Larsson, Carl-Magnus
    et al.
    Brewitz, Erica
    Jones, Celia
    Avila, R.
    Beresford, Nick
    Brown, Justin
    Fortin, C.
    Garnier-Laplace, Jacqueline
    Gilek, Michael
    Södertörn University College, Avdelning Naturvetenskap.
    Oughton, Deborah
    Pentreath, J.
    Pröhl, Gerhard
    Sundell-Bergman, S.
    Zinger-Gize, Irène
    Overview of programmes for the assessment of risks to the environmentfrom ionising radiation and hazardouschemicals: FASSET deliverable 2: part 22002Report (Other academic)
  • 131.
    Larsson, Sofia L
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Nygård, Odd
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Proposed secondary structure of eukaryote specific expansion segment 15 in 28S rRNA from mice, rats, and rabbits2001In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 40, no 10, p. 3222-3231Article in journal (Refereed)
    Abstract [en]

    The expansion segments in eukaryotic ribosomal RNAs are additional RNA sequences not found in the RNA core common to both prokaryotes and eukaryotes. These regions show large species-dependent variations in sequence and size. This makes it difficult to create secondary structure models for the expansion segments exclusively based on phylogenetic sequence comparison. Here we have used a combination of experimental data and computational methods to generate secondary structure models for expansion segment 15 in 28S rRNA in mice, rats, and rabbits. The experimental data were collected using the structure sensitive reagents DMS, CMCT, kethoxal, micrococcal nuclease, RNase TI, RNase CL3. RNase VI, and lead(II) acetate, ES15 was folded with the computer program RNAStructure 3.5 using modification data and phylogenetic similarities between different ES15 sequences. This program uses energy minimization to find the most stable secondary structure of an RNA sequence. The presented secondary structure models include several common structural motifs, but they also have characteristics unique to each organism. Overall, the secondary structure models showed indications of an energetically stable but dynamic structure, easily accessible from the solution by the modification reagents, suggesting that the expansion segment is located on the ribosomal surface.

  • 132.
    Larsson, Sofia L
    et al.
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Sloma, Marika S
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Nygård, Odd
    Södertörn University, Avdelning Naturvetenskap.
    Conformational changes in the structure of domains II and V of 28S rRNA in ribosomes treated with the translational inhibitors ricin or alpha-sarcin2002In: Biochimica et Biophysica Acta, Gene Structure and Expression, ISSN 0167-4781, E-ISSN 1879-2634, Vol. 1577, no 1, p. 53-62Article in journal (Refereed)
    Abstract [en]

    Ricin and alpha-sarcin modify neighbouring sites in the so-called sarcin/ricin (S/R) loop of 28S rRNA, thereby destroying the necessary dynamic flexibility of the ribosome, and inhibiting the elongation factor assisted steps of the elongation cycle. The effects of the two translational inhibitors on the conformation of domains 11 and V of 28 S rRNA were investigated by chemical modification of programmed mouse ribosomes pretreated with ricin or alpha-sarcin. The results showed that the two ribosome-inactivating proteins (RIP) influenced the structure of the ribosomal RNA. Inhibitor-affected sites were located at or near sites previously proposed to be involved in functional domains. The modification patterns obtained after ricin or alpha-sarcin treatment of ribosomes were partially overlapping. However, there were several inhibitor-specific structural changes in 28S rRNA. Such changes were found at positions located at the GTPase activating centre of the ribosome and in the S/R domain, indicating that the structure in these regions of the ribosomes differed after treatment with the two inhibitors. These changes are consistent with ricin and alpha-sarcin having specific effects on eEF-2 and eEF-1 interaction with the ribosome, respectively.

  • 133.
    Le Rouzic, E
    et al.
    Université Paris 5, Paris, France.
    Mousnier, A
    Université Paris VI and Université Paris VII, Paris, France.
    Rustum, Cecilia
    Södertörn University, Avdelning Naturvetenskap. Stockholm University.
    Stutz, F
    Université Paris 5, Paris, France.
    Hallberg, Einar
    Stockholm University.
    Dargemont, C
    Université Paris VI and Université Paris VII, Paris, France.
    Benichou, S
    Université Paris 5, Paris, France.
    Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG12002In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 47, p. 45091-45098Article in journal (Refereed)
    Abstract [en]

    The HIV-1 genome contains several genes coding for auxiliary proteins, including the small Vpr protein. Vpr affects the integrity of the nuclear envelope and participates in the nuclear translocation of the preintegration complex containing the viral DNA. Here, we show by photobleaching experiments performed on living cells expressing a Vpr-green fluorescent protein fusion that the protein shuttles between the nucleus and the cytoplasm, but a significant fraction is concentrated at the nuclear envelope, supporting the hypothesis that Vpr interacts with components of the nuclear pore complex. An interaction between HIV-1 Vpr and the human nucleoporin CG1 (hCG1) was revealed in the yeast two-hybrid system, and then confirmed both in vitro and in transfected cells. This interaction does not involve the FG repeat domain of hCG1 but rather the N-terminal region of the protein. Using a nuclear import assay based on digitonin-permeabilized cells, we demonstrate that hCG1 participates in the docking of Vpr at the nuclear envelope. This association of Vpr with a component of the nuclear pore complex may contribute to the disruption of the nuclear envelope and to the nuclear import of the viral DNA.

  • 134. Lebbink, J H G
    et al.
    Consalvi, V
    Chiaraluce, R
    Berndt, Kurt D
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Ladenstein, R
    Structural and thermodynamic studies on a salt-bridge triad in the NADP-binding domain of glutamate dehydrogenase from Thermotoga maritima: Cooperativity and electrostatic contribution to stability2002In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, no 52, p. 15524-15535Article in journal (Refereed)
    Abstract [en]

    Cooperative interactions within ion-pair networks of hyperthermostable proteins are thought to be a major determinant for extreme protein stability. While the favorable thermodynamic contributions of optimized electrostatics in general as well as those of pairwise interactions have been documented, cooperativity between pairwise interactions has not yet been studied thermodynamically in proteins from hyperthermophiles. In this study we use the isolated cofactor binding domain of glutamate dehydrogenase from the hyperthermophilic bacterium Thermotoga maritima to analyze pairwise and cooperative interactions within the salt-bridge triad Arg190-Glu231-Lys193. The X-ray structure of the domain was solved at 1.43 Angstrom and reveals the salt-bridge network with surrounding solvent molecules in detail. All three participating charges in the network were mutated to alanine in all combinations. The X-ray structure of the variant lacking all three charges reveals that the removal of the side chains has no effect on the overall conformation of the protein. Using solvent denaturation and thermodynamic cycles, the interaction energies between each pair of residues in the network were determined in the presence and in the absence of the third residue. Both the Arg190-Glu231 ion pair and the Lys193-Glu231 salt bridge in the absence of the third residue, contribute favorably to the free energy for unfolding of the domain in urea. Using guanidinium chloride as denaturant reveals a strong cooperativity between the two ion-pair interactions, the presence of the second ion pair converts the first interaction from destabilizing into stabilizing by as much as 1.09 kcal/mol. The different energetics of the salt-bridge triad in urea and GdmCl are discussed with reference to the observed anion binding in the crystal structure at high ionic strength and their possible role in a highly charged, high-temperature environment such as the cytoplasm of hyperthermophiles.

  • 135.
    Lehtilä, Kari
    Södertörn University, Avdelning Naturvetenskap.
    Precision of herbivore tolerance experiments with imposed and natural damage2003In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 57, no 3, p. 677-680Article in journal (Refereed)
    Abstract [en]

    Tiffin and Inouye (2000) discussed the use of natural and imposed (controlled) damage in experiments of herbivore tolerance. They constructed a statistical model of the effect of herbivory on plant fitness, including damage level and an environmental factor as the independent factors, in which tolerance is defined as a slope of the regression line when damage level is regressed with plant fitness. They claim that while experiments with imposed damage are more accurate (i.e., they give a more correct estimate of tolerance), experiments with natural damage are more precise under a wide range of parameter values (i.e., tolerance estimates explain a larger part of variation in fitness). I show, however, that experiments with imposed damage are less precise only when an experimenter uses an experimental design that has weaker statistical power than in experiments with natural herbivory. The experimenter can nevertheless control the damage levels to optimize the experimental designs. For instance, when half of the experimental plants are left undamaged and the other half treated with maximal relevant damage level, experiments with imposed damage are almost always much more precise than experiments with natural damage.

  • 136. Leimu, Roosa
    et al.
    Syrjänen, Kimmo
    Ehrlén, Johan
    Lehtilä, Kari
    Södertörn University, Avdelning Naturvetenskap.
    Pre-dispersal seed predation in Primula veris: among-population variation in damage intensity and selection on flower number2002In: Oecologia, ISSN 0029-8549, E-ISSN 1432-1939, Vol. 133, no 4, p. 510-516Article in journal (Refereed)
    Abstract [en]

    The geographic mosaic theory of co-evolution states that evolution of interactions is driven by geographical variation in interactions between species. We investigated whether the intensity of pre-dispersal seed predation differed among nine Primula veris populations over 5 years, and whether such differences lead to geographical variation in selection on flower number. Seed predation intensity differed significantly among years and populations, and it increased with canopy closure and decreased with the density of the field layer vegetation. Individuals in open habitats also produced the highest number of flowers. Moreover, the phenotypic selection on flower number differed among years and populations. In populations of closed habitats, with high seed predation pressure, the increased number of flowers was often correlated with an increased number of damaged capsules. However, an increased flower number did not result in fewer intact fruits due to seed predation in any population.

  • 137. Li, J J
    et al.
    Bauer, S H J
    Månsson, Martin
    Södertörn University, Avdelning Naturvetenskap.
    Moxon, E R
    Richards, J C
    Schweda, Elke K H
    Södertörn University, Avdelning Naturvetenskap.
    Glycine is a common substituent of the inner core in Haemophilus influenzae lipopolysaccharide2001In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 11, no 12, p. 1009-1015Article in journal (Refereed)
    Abstract [en]

    A survey of both typeable and nontypeable strainsof Haemophilus influenzae indicated that they contain glycine (Gly) in their lipopolysaccharide (LPS). Significant amounts (30-250 pmol Gly/mug LPS) were determined by high-performance anion-exchange chromatography using pulsed amperometric detection after treatment of the LPS with mild alkali. Oligosaccharides obtained from LPS after mild acid hydrolysis and gel filtration chromatography were investigated by electrospray ionization mass spectrometry (ESI-MS) and capillary electrophoresis (CE) ESI-MS. In all cases, molecular ions corresponding to the major glycoforms were identified and were accompanied by ions differing by 57 Da, thus indicating the presence of glycine. The position of glycine in these glycoforms was determined by CE-ESI-MS/MS analyses. It was found that, depending on strain, glycine can substitute each of the heptoses of the inner-core element, L-alpha-D-Hepp-(1-->2)-[PEtn-->6]-L-alpha-D-Hepp-(1-->3)-L-alpha-D-Hepp- (1-->5)-alpha-Kdo of H. influenzae LPS as well as Kdo. In some strains, mixtures of monosubstituted Gly-containing glycoforms having different substitution patterns were identified.

  • 138. Liao, Dezhong Joshua
    et al.
    Blanck, Agneta
    Eneroth, Peter
    Gustafsson, Jan-Åke
    Porsch Hällström, Inger
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat2001In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 109, no 9, p. 943-947Article in journal (Refereed)
    Abstract [en]

    The acute toxicity of diethylnitrosamine (DEN) to the liver has been well documented in the literature, but whether DEN also affects the endocrine parameters has been addressed in only a few studies. We thus investigated the effects of DEN on pituitary, serum hormone levels, and certain sex-differentiated liver enzymes in this study. Adult male Wister rats were intraperitoneally injected with DEN at a single dose of 200 mg/kg and were sacrificed at 1, 3, 7, and 35 days after injection; DEN-treated females were included as controls at days 7 and 35. Electron microscopic observation showed that during the first week after injection, all types of granular cells of the anterior pituitary in male animals exhibited cellular damage, including disrupted organelles and cellular structure, as well as pyknotic or lytic nuclei. Many undamaged secretory cells exhibited dilated endoplasmic reticula, hypertrophic Golgi complexes, and peripheral location of secretory granules, which usually are morphologic features of increased cellular activities. In male rats, the serum level of total testosterone decreased and the corticosterone increased I day after DEN treatment. The serum level of growth hormone (GH) decreased and the prolactin level increased on day 3. The hepatic expression of the male-specific cytochrome P450 2C11 (CYP2C11) decreased to 1-5% of the normal levels during the first week and was still 50% lower than the normal level on day 35, whereas the female-specific CYP2C12 expression increased only slightly. Activities of the male predominant 16 alpha, 16 beta, and 6 beta hydroxylation of androstenedione by microsome decreased in an in vitro assay, whereas the non-sex-differentiated 7 alpha hydroxylation and the female-predominant 5 alpha reduction of androstenedione were unaffected. In female rats, decreased serum GH level was observed on day 7. The CYP2C12 expression in females was decreased to about 1% and 80% of the normal levels on day 7 and day 35, respectively, but the CYP2C11 expression was unchanged. These data suggest that in male rats, DEN treatment may cause pituitary damage, disturb serum hormone levels, and induce long-lasting reduction of sexual dimorphism in certain liver functions.

  • 139. Lind, U
    et al.
    Greenidge, P
    Gillner, M
    Koehler, K F
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Carlstedt-Duke, J
    Functional probing of the human glucocorticoid receptor steroid-interacting surface by site-directed mutagenesis - Gln-642 plays an important role in steroid recognition and binding2000In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, no 25, p. 19041-19049Article in journal (Refereed)
    Abstract [en]

    To elucidate which amino acids in the glucocorticoid receptor ligand-binding domain might be involved in determining steroid binding specificity by interaction with the D-ring of glucocorticoids, we have performed site-directed mutagenesis of the four amino acids Met-560, Met-639, Gln-642, and Thr-739 based on their proximity to the steroid in a model structure. Mutations of these residues affected steroid binding affinity, specificity, and/or steroid-dependent transactivation. The results indicate that these residues are located in close proximity to the ligand and appear to play a role in steroid recognition and/or transactivating sensitivity, possibly by changes in the steroid-dependent conformational change of this region, resulting in the formation of the AF-2 site. Mutation of Gln-642 resulted in a marked decrease in affinity for steroids containing a 17 alpha-OH group. This effect was alleviated by the presence of a 16 alpha-CH3 group to a varying degree. Thr-739 appears to form a hydrogen bond with the 21-OH group of the steroid, as well as possibly forming hydrophobic interactions with the steroid, Met-EGO and Met-639 appear to form hydrophobic interactions with the D-ring of the steroid, although the nature of these interactions cannot be characterized in more detail at this point.

  • 140. Lind, U.
    et al.
    Greenidge, P.
    Gustafsson, J. -A
    Wright, Anthony P. H.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Instiute.
    Carlstedt-Duke, J.
    Valine 571 functions as a regional organizer in programming the glucocorticoid receptor for differential binding of glucocorticoids and mineralocorticoids1999In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 274, no 26, p. 18515-18523Article in journal (Refereed)
    Abstract [en]

    The glucocorticoid receptor (GR) interacts specifically with glucocorticoids, whereas its closest relative, the mineralocorticoid receptor (MR), interacts with both glucocorticoids and mineralocorticoids, such as aldosterone. To investigate the mechanism underlying the glucocorticoid/mineralocorticoid specificity of the GR, we used a yeast model system to screen for GR ligand-binding domain mutants, substituted with MR residues in the segment 565-574, that can be efficiently activated by aldosterone. In all such increased activity mutants, valine 571 was replaced by methionine, even though most mutants also contained substitutions of other residues with their MR counterparts. Further analysis in yeast and COS-7 cells has revealed that the identity of residue 571 determines the behavior of other MR substituted residues in the 565-574 segment. Generally, MR substitutions in this region are only consistent with aldosterone binding if residue 571 is also replaced with methionine (MR conformation). If residue 571 is valine (GR conformation), most other MR substitution mutants drastically reduce interaction with both mineralocorticoid and glucocorticoid hormones. Based on these functional data, we hypothesize that residue 571 functions as a regional organizer involved in discriminating between glucocorticoid and mineralocorticoid hormones. We have used a molecular model of the GR ligand-binding domain in an attempt to interpret our functional data in structural terms.

  • 141. Lohm, Jakob
    et al.
    Grahn, Mats
    Södertörn University, Avdelning Naturvetenskap.
    Langefors, Åsa
    Andersen, Øivind
    Storset, Arne
    von Schantz, Torbjörn
    Experimental evidence for major histocompatibility complex-allele-specific resistance to a bacterial infection2002In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 269, no 1504, p. 2029-2033Article in journal (Refereed)
    Abstract [en]

    The extreme polymorphism found at some major histocompatibility complex (MHC) loci is believed to be maintained by balancing selection caused by infectious pathogens. Experimental support for this is inconclusive. We have studied the interaction between certain MHC alleles and the bacterium Aeromonas salmonicida, which causes the severe disease furunculosis, in Atlantic salmon (Salmo salar L.). We designed full-sibling broods consisting of combinations of homozygote and heterozygote genotypes with respect to resistance or susceptibility alleles. The juveniles were experimentally infected with A. salmonicida and their individual survival was monitored. By comparing full siblings carrying different MHC genotypes the effects on survival due to other segregating genes were minimized. We show that a pathogen has the potential to cause very intense selection pressure on particular MHC alleles; the relative fitness difference between individuals carrying different MHC alleles was as high as 0.5. A co-dominant pattern of disease resistance/susceptibility was found, indicative of qualitative difference in the immune response between individuals carrying the high- and low-resistance alleles. Rather unexpectedly, survival was not higher among heterozygous individuals as compared with homozygous ones.

  • 142.
    Lowder, M
    et al.
    University of North Carolina at Charlotte, Charlotte, USA.
    Unge, A
    Stockholms universitet.
    Maraha, Ninwe
    Södertörn University, Avdelning Naturvetenskap.
    Jansson, Janet K
    Södertörn University, Avdelning Naturvetenskap. Stockholms universitet.
    Swiggett, J
    Carolinas Medical Center, Charlotte, USA.
    Oliver, J D
    University of North Carolina at Charlotte, Charlotte, USA.
    Effect of starvation and the viable-but-nonculturable state on green fluorescent protein (GFP) fluorescence in GFP-tagged Pseudomonas fluorescens A5062000In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 66, no 8, p. 3160-3165Article in journal (Refereed)
    Abstract [en]

    The green fluorescent protein (GFP) gene, gfp, of the jellyfish Aequorea victoria is being used as a reporter system for gene expression and as a marker for tracking prokaryotes and eukaryotes. Cells that have been genetically altered with the gfp gene produce a protein that fluoresces when it is excited by UV light. This unique phenotype allows gth-tagged cells to be specifically monitored by nondestructive means, In this study we determined whether a gfp-tagged strain of Pseudomonas fluorescens continued to fluoresce under conditions under which the cells were starved, viable but nonculturable (VBNC), or dead. Epifluorescent microscopy, flow cytometry, and spectrofluorometry were used to measure fluorescence intensity in starved, VBNC, and dead or dying cells. Results obtained by using how cytometry indicated that microcosms containing VBNC cells, which were obtained by incubation under stress conditions (starvation at 37.5 degrees C), fluoresced at an intensity that mas at least 80% of the intensity of nonstressed cultures, Similarly, microcosms containing starved cells incubated at 5 and 30 degrees C had fluorescence intensities that were 90 to 110% of the intensity of nonstressed cells. VBNC cells remained fluorescent during the entire 6-month incubation period. in addition, cells starved at 5 or 30 degrees C remained fluorescent for at least 11 months. Treatment of the cells with UV light or incubation at 39 or 50 degrees C resulted in a loss of GFP from the cells. There was a strong correlation between cell death and leakage of GFP from the cells, although the extent of leakage varied depending on the treatment, Most dead cells were not GFP fluorescent, but a small proportion of the dead cells retained some GFP at a lower concentration than the concentration in live cells, Our results suggest that gfp-tagged cells remain fluorescent following starvation and entry into the VBNC state but that fluorescence is lost when the cells die, presumably because membrane integrity is lost.

  • 143.
    Lund, Bodil
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Different roles of enterococcus faecium from a human perspective2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Food supplements containing viable bacteria, so called probiotics, have been suggested to have beneficial health effects due to their influence on the normal microflora. However, there has been safety concern regarding probiotics containing Enterococcus faecium. Although part of the normal intestinal microflora in humans, enterococci can cause infections such as urinary tract infections, septicaemia, and endocarditis. Enterococci are also inclined to develop antibiotic resistance and their hardy nature promotes survival and dissemination in the hospital setting. Although the importance of E.faecium as a bloodstream isolate is increasing, little regarding its virulence is known. One virulence trait attributed to E. faecium is the enterococcal surface protein, Esp, encoded by the esp gene. Since enterococci have different roles from the human perspective, such as occurrence in food, as probiotic strains, members of the normal intestinal microflora, and as the cause of nosocomial infections, it is important to study differences and similarities between strains of different origin. The aims of the present investigation were to study some safety aspects of a probiotic product containing Efaecium, the colonization and transmission of enterococci from a nosocomial perspective, and differences between E.faecium isolates of different origin in some characteristics of probable importance for virulence. Faecal samples were collected from healthy volunteers administered an E. faecium probiotic. Half of the volunteers received simultaneous peroral vancomycin. The E. faecium isolates were subtyped and an in vitro conjugation assay was performed. The investigated strain could survive gastrointestinal transit in humans, and intake temporarily increased the number of enterococci in the faecal microflora. The vancomycin administration prevented detection of the probiotic strain. The probiotic strain could gain the vanA gene cluster under in vitro conditions. Samples from the respiratory tract and stomach were collected from 20 consecutive patients undergoing mechanical ventilation. The enterococci isolated were subsequently subtyped. Seventeen of the 20 subjects were colonized with enterococci in the respiratory tract. Genotype analyses suggested that 13 patients were involved in a transmission event, including all patients intubated more than 12 days. The E. faecium isolates were more resistant to antimicrobial agents compared to E. faecalis. The E. faecium isolates from different origins, i.e., infections, faeces, and probiotic products, were investigated for the presence of esp, their ability to conjugate, and adhere to epithelial cells in vitro. The esp gene was significantly more common among blood isolates. E. faecium strains enriched with esp adhered significantly better, were less genetically diverse, and had a higher conjugation frequency compared to esp-negative blood isolates. Antibiotic resistance was only detected among the infection-derived isolates. The adhesion among esp-negative isolates from the normal microflora was higher compared to the esp-negative bacteraemia isolates. In conclusion, the investigated probiotic E. faecium strain can survive gastrointestinal transit in humans, and intake may transiently increase the number of enterococci in the faecal microflora. The same strain can gain the vanA operon. Enterococci are frequently disseminated between mechanically ventilated patients, and isolates from different subpopulations seem to have different characteristics in terms of occurrence of esp, adhesion properties, antibiotic resistance, and conjugation frequencies.

  • 144.
    Lund, Bodil
    et al.
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Adamsson, I
    Huddinge University Hospital, Karolinska Institutet.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Gastrointestinal transit survival of an Enterococcus faecium probiotic strain administered with or without vancomycin2002In: International Journal of Food Microbiology, ISSN 0168-1605, E-ISSN 1879-3460, Vol. 77, no 1-2, p. 109-115Article in journal (Refereed)
    Abstract [en]

    The primary aim of this study was to evaluate if an ingested probiotic, containing viable Enterococcus faecium could survive gastrointestinal transit and if so, correlate the amount of the recovered probiotic strain with the host's own enterococci. The second aim was to investigate if simultaneous vancomycin intake influenced the survival and persistence of the probiotic strain and the stability of endogenous enterococci strains. Twenty healthy volunteers were given the probiotic product once daily for 10 days. Half of the subjects were simultaneously given vancomycin. Isolates of E. faecium strains were genotypically or phenotypically analysed with pulsed-field gel electrophoresis (PFGE) and the PhenePlate(TM) system, respectively. In eight of the ten volunteers given only the probiotic, the ingested E. faecium could be detected on day 10, while in none on day 31. From subjects given both probiotic and vancomycin no ingested E. faecium could be detected on day 10 or day 31. The estimated amount of ingested E. faecium recovered from faeces on day 10 ranged from 1.2 x 10(3) to 4.2 x 10(6) colony forming units per gram faeces, which in several cases were a substantial part of the total amount of E. faecium. The E. faecium isolated before probiotic plus vancomycin administration showed no close relationship to the ones isolated 3 weeks after ceased intake in any subjects. In conclusion, the ingested E. faecium strain can survive gastrointestinal transit. After intake, the E. faecium probiotic strain might become a large part of the total E, faecium population. The occurrence of the probiotic strain in the human gut seems to be transient after intake stop. Re-colonization of E. faecium after simultaneous probiotic plus vancomycin intake occurs mainly with strains without close genetic relationship to the strains harboured before treatment or to the ingested E. faecium strain.

  • 145.
    Lund, Bodil
    et al.
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Agvald-Öhman, C
    Huddinge University Hospital, Karolinska Institutet.
    Hultberg, Anna
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Frequent transmission of enterococcal strains between mechanically ventilated patients treated at an intensive care unit2002In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 40, no 6, p. 2084-2088Article in journal (Refereed)
    Abstract [en]

    The objectives of this investigation were to study the respiratory tract colonization and transmission of enterococci between 20 patients treated with mechanical ventilation at an intensive care unit (ICU), to compare genotyping with phenotyping, and to determine the antibiotic susceptibilities of the isolated enterococci. Samples were collected from the oropharynx, stomach, subglottic space, and trachea within 24 It of intubation, every third day until day 18, and thereafter every fifth day until day 33. Enterococcal isolates (n = 170) were analyzed by pulsed-field gel electrophoresis and with the PhenePlate (PhP) system. The antimicrobial susceptibilities to five agents were determined. Seventeen of the 20 subjects were colonized with enterococci in the respiratory tract; 12 were colonized in the lower respiratory tract. Genotype analyses suggested that 13 patients were involved in a transmission event, including all patients intubated more than 12 days. In conclusion, colonization of resistant enterococci in the respiratory tract of intubated patients treated at an ICU was common. Transmission of enterococci between patients occurred frequently. Prolonged intubation period seems to be a risk factor for enterococcal cross-transmission.

  • 146.
    Lund, Bodil
    et al.
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap. Huddinge University Hospital, Karolinska Institutet.
    Bloodstream isolates of Enterococcus faecium enriched with the enterococcal surface protein gene, esp, show increased adhesion to eukaryotic cells2003In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 41, no 11, p. 5183-5185Article in journal (Refereed)
    Abstract [en]

    Infection-derived Enterococcus faecium strains enriched with esp had increased ability to adhere to Caco-2 cells (P < 0.05) and were less genetically diverse than esp-negative isolates. esp-negative E. faecium fecal isolates from healthy individuals adhered significantly better than esp-negative infection isolates (P < 0.05), indicating additional factors of importance to adhesion.

  • 147.
    Lund, Bodil
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet, Huddinge University Hospital.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet, Huddinge University Hospital.
    Probiotic Enterococcus faecium strain is a possible recipient of the vanA gene cluster2001In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 32, no 9, p. 1384-1385Article in journal (Refereed)
    Abstract [en]

    The characteristics of Enterococcus faecium have led to concern regarding the safety of probiotics that contain this bacterium. The results of an in vitro filter mating assay indicate that a probiotic E. faecium strain might be a potential recipient of vancomycin resistance genes.

  • 148.
    Lund, Bodil
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet, Huddinge University Hospital.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet, Huddinge University Hospital.
    Barkholt, L
    Karolinska Institutet, Huddinge University Hospital.
    Nord, C E
    Karolinska Institutet, Huddinge University Hospital.
    Tvede, M
    Rigshospitalet, Copenhagen, Denmark.
    Poulsen, R L
    Statens Seruminstitut, Copenhagen, Denmark.
    Impact on human intestinal microflora of an Enterococcus faecium probiotic and vancomycin2000In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 32, no 6, p. 627-632Article in journal (Refereed)
    Abstract [en]

    The aims of this study were to evaluate the impact of a fermented milk product containing viable Enterococcus faecium on human intestinal microflora and to evaluate any risk of development of vancomycin-resistant enterococci (VRE). Twenty Danish and 20 Swedish healthy volunteers were given 150 mi of the fermented mill;. product once daily, equivalent to a daily dose of 4.5 x 10(9) to 7.5 x 10(9) CFU E. faecium, for 10 d. Half of the volunteers also received 125 mg vancomycin orally q.i.d. for 10 d. Faecal samples were collected on day 0 before intake, on day 10 directly after end of intake and on day 31, 3 weeks after the end of the experiment. There,Fas a significant increase in the total number of enterococci on day 10 (p < 0.01) in the group receiving only the E. faecium supplement, but 3 weeks later the level was as before intake. In the vancomycin group, the total number of enterococci was reduced on day 10 (p < 0.01) but had increased on day 31 (p < 0.01) in relation to day 0. In none of the Swedish and 4 of the Danish volunteers, VRE were sporadically detected, but without relation to intake of the probiotic or vancomycin. In healthy young Danish individuals the VRE carrier rate tended to be higher than previously found.

  • 149.
    Lund, Bodil
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Edlund, Charlotta
    Södertörn University, Avdelning Naturvetenskap.
    Rynnel-Dagoo, B
    Lundgren, Y
    Sterner, J
    Nord, C E
    Ecological effects on the oro- and nasopharyngeal microflora in children after treatment of acute otitis media with cefuroxime axetil or amoxycillin-clavulanate as suspensions2001In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 7, no 5, p. 230-237Article in journal (Refereed)
    Abstract [en]

    Objective To evaluate if the extent of normal microflora disturbances differed between treatment with amoxycillin-clavulanate administered in an active form and cefuroxime axetil administered as an inactive prodrug. Methods Twenty-eight children, 0.5-5 years old, diagnosed with acute otitis media (AOM), were treated with either amoxycillin-clavulanate (13.3 mg/kg 3 times daily) or cefuroxime axetil (15 mg/kg twice daily) for 7 days. Saliva samples and nasopharyngeal swabs were collected before, directly after and 2 weeks after treatment. The saliva samples were quantitatively and qualitatively analyzed and the nasopharyngeal swabs were qualitatively analyzed. All isolated strains were tested for beta -lactamase production. Results Both treatment regimens gave rise to similar alterations of the normal oropharyngeal microflora. In both groups, the amount of Streptococcus salivarius was significantly reduced (P < 0.05). The most common causative pathogens of acute otitis were S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. On the day of enrollment, approximately half of the patients, in both groups, were infected with more than one pathogen. The rate of infection or colonization with more than one potential pathogen was low on day 7 but recurred 2 weeks after treatment to similar levels as on day 0. The total number of patients with reinfection, recolonization or recurrence of pathogens on day 21 was 11/12 in the amoxycillin-clavulanate group and 4/7 in the cefuroxime axetil group. The most common <beta>-lactamase producer was M. catarrhalis. Conclusion The local high concentration of antibiotics in the oropharynx immediately after intake of antibiotic suspensions seem to have little or no impact on the extent of disturbance of the microflora in this region. Children of this age group seem prone to either reinfection, recolonization or persistence of pathogens within 2 weeks after treatment. Furthermore, co-infection with more than one pathogen seems common in children with AOM and infection with beta -lactamase producing microorganisms occurs frequently.

  • 150.
    Lönn, Mikael
    et al.
    Södertörn University, Avdelning Naturvetenskap.
    Prentice, Honor C.
    Gene diversity and demographic turnover in central and peripheral populations of the perennial herb, Gypsophila fastigiata2002In: Oikos, ISSN 0030-1299, E-ISSN 1600-0706, Vol. 99, no 3, p. 489-498Article in journal (Refereed)
    Abstract [en]

    Within-population gene diversity (HS) was estimated (using allozyme markers) for 16 populations of the perennial, outcrossing plant, Gypsophila fastigiata, on the Baltic island of Öland. The populations were characterized by data on extent, density, life-stages, and habitat diversity. Populations were classed as central or peripheral in relation to the distribution of “alvar” (habitats with shallow, calcareous soils on limestone bedrock) on southern Öland. Three minimal adequate models were used to explain HS and the proportions of juveniles and dead adults. In the first model, HS was significantly lower in peripheral populations and there were no significant additional effects of other explanatory variables. The lower diversity in peripheral populations can be explained by a combination of genetic drift (in populations that vary in size in response to habitat fragmentation) and lower levels of interpopulation gene flow than in central populations. In the two life-stage models, peripheral populations had significantly larger proportions of both juveniles and dead adults – indicating a greater demographic turnover than in the central populations. There were also significant effects of HS and species diversity on the proportion of juveniles. The central or peripheral position of populations is the strongest predictor of both within-population gene diversity and life-stage dynamics in Öland G. fastigiata.

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