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Sökning: WFRF:(Müller Heiko)

  • Resultat 11-20 av 21
  • Föregående 1[2]3Nästa
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11.
  • Brenner, David, et al. (författare)
  • Hot-spot KIF5A mutations cause familial ALS
  • 2018
  • Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
  • Tidskriftsartikel (refereegranskat)abstract
    • Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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12.
  • Fortmann, Jutta, et al. (författare)
  • Demo Hour
  • 2015
  • Ingår i: Interactions. - : Association for Computing Machinery (ACM). - 1072-5520. ; 22:1, January + February 2015, s. 6-9
  • Tidskriftsartikel (refereegranskat)abstract
    • NordiCHI'14 conference attendees got hands-on experience with a number of great new interactive systems. Among the accepted poster, video, and demo submissions, we selected the following four prototypes to illustrate the high-quality design research displayed during the conference, which was held in Helsinki, Finland, October 26--30, 2014.
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13.
  • Herwald, Heiko, et al. (författare)
  • Activation of the contact-phase system on bacterial surfaces - A clue to serious comlications in infections deseases
  • 1998
  • Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956. ; 4:3, s. 298-302
  • Tidskriftsartikel (refereegranskat)abstract
    • Fever, hypotension and bleeding disorders are common symptoms of sepsis and septic shock. The activation of the contact-phase system is thought to contribute to the development of these severe disease states by triggering proinflammatory and procoagulatory cascades; however, the underlying molecular mechanisms are obscure. Here we report that the components of the contact-phase system are assembled on the surface of Escherichia coil and Salmonella through their specific interactions with fibrous bacterial surface proteins, curli and fimbriae. As a consequence, the proinflammatory pathway is activated through the release of bradykinin, a potent inducer of fever, pain and hypotension. Absorption of contact-phase proteins and fibrinogen by bacterial surface proteins depletes relevant coagulation factors and causes a hypocoagulatory state. Thus, the complex interplay of microbe surface proteins and host contact-phase factors may contribute to the symptoms of sepsis and septic shock.
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14.
  • Herwald, Heiko, et al. (författare)
  • Streptococcal cysteine proteinase releases kinins: a novel virulence mechanism
  • 1996
  • Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538. ; 184:2, s. 665-673
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous work has indicated a crucial role for the extracellular cysteine proteinase of Streptococcus pyogenes in the pathogenicity and virulence of this important human pathogen. Here we find that the purified streptococcal cysteine proteinase releases biologically active kinins from their purified precursor protein, H-kininogen, in vitro, and from kininogens present in the human plasma, ex vivo. Kinin liberation in the plasma is due to the direct action of the streptococcal proteinase on the kininogens, and does not involve the previous activation of plasma prekallikrein, the physiological plasma kininogenase. Judged from the amount of released plasma kinins the bacterial proteinase is highly efficient in its action. This is also the case in vivo. Injection of the purified cysteine proteinase into the peritoneal cavity of mice resulted in a progressive cleavage of plasma kininogens and the concomitant release of kinins over a period of 5 h. No kininogen degradation was seen in mice when the cysteine proteinase was inactivated by the specific inhibitor, Z-Leu-Val-Gly-CHN2, before administration. Intraperitoneal administration into mice of living S. pyogenes bacteria producing the cysteine proteinase induced a rapid breakdown of endogenous plasma kininogens and release of kinins. Kinins are hypotensive, they increase vascular permeability, contract smooth muscle, and induce fever and pain. The release of kinins by the cysteine proteinase of S. pyogenes could therefore represent an important and previously unknown virulence mechanism in S. pyogenes infections.
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15.
  • Johnson, Nichola, et al. (författare)
  • Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study
  • 2014
  • Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411. ; 16:3, s. R51-
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age <= 50 years. Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P-trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P-trend = 0.005) but not cases (P-trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P-het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age >= 15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; P-trend = 0.002) but not for those who had their menarche age <= 11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; P-trend = 0.29). Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
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16.
  • Kahn, Robin, et al. (författare)
  • Contact-system activation in children with vasculitis.
  • 2002
  • Ingår i: The Lancet. - : Elsevier. - 1474-547X. ; 360:9332, s. 535-541
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The contact system triggers the kallikrein-kinin cascade, liberating bradykinin from high-molecular-weight kininogen. Effectors of the contact system have proinflammatory and vasoactive properties. Vasculitis is a condition characterised by inflammation around vessel walls, leading to secondary tissue damage for which the underlying molecular mechanisms are poorly understood. Our aim was to investigate contact-system activation in children with vasculitis. METHODS: We compared 17 children, aged 4-19 years, with vasculitis, engaging the skin, joints, intestines, or kidneys, with 21 controls, aged 2-18 years. We analysed proteolysis of high-molecular-weight kininogen by immunoblotting. Plasma bradykinin concentrations were quantified by ELISA. Kidney and skin biopsies were stained in situ for kinins. Concentrations of heparin binding protein (HBP) were quantified by ELISA. FINDINGS: We noted extensive proteolysis of high-molecular-weight kininogen in the plasma of 13 of 17 patients, but in only one of 21 controls (p<0.0001). Bradykinin concentrations were higher in the patients' plasma (median 320 ng/L, range <1-19680) than in plasma from controls (11 ng/L, <1-304; p=0.0004). Patients had local release of kinins at sites of inflammation in kidney and skin biopsies. HBP values were raised in patients (17.4 microg/L, 5.4-237.6) compared with controls (6 microg/L, 2.5-43.4; p=0.008). INTERPRETATION: Activation of the contact system could play a part in the pathogenesis of vasculitis, and explain the inflammation, pain, vasodilatation, and oedema seen in patients.
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17.
  • Meyer, Kerstin B., et al. (författare)
  • Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1
  • 2013
  • Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 93:6, s. 1046-1060
  • Tidskriftsartikel (refereegranskat)abstract
    • The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ER alpha to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.
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18.
  • Müller, Florian, et al. (författare)
  • Towards a conceptual framework for explaining variation in nocturnal departure time of songbird migrants
  • 2016
  • Ingår i: Movement Ecology. - : BioMed Central (BMC). - 2051-3933. ; 4:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Most songbird migrants travel between their breeding areas and wintering grounds by a series of nocturnal flights. The exact nocturnal departure time for these flights varies considerably between individuals even of the same species. Although the basic circannual and circadian rhythms of songbirds, their adaptation to migration, and the factors influencing the birds' day-to-day departure decision are reasonably well studied, we do not understand how birds time their departures within the night. These decisions are crucial, because the nocturnal departure time defines the potential flight duration of the migratory night. The distances covered during the nocturnal migratory flights in the course of migration in turn directly affect the overall speed of migration. To understand the factors influencing the arrival of the birds in the breeding/wintering areas, we need to investigate the mechanisms that control nocturnal departure time. Here, we provide the first conceptual framework for explaining the variation commonly observed in this migratory trait. The basic schedule of nocturnal departure is likely regulated by both the circannual and circadian rhythms of the innate migration program. We postulate that the endogenously controlled schedule of nocturnal departures is modified by intrinsic and extrinsic factors. So far there is only correlative evidence that birds with a high fuel load or a considerable increase in fuel load and significant wind (flow) assistance towards their migratory goal depart early within the night. In contrast, birds migrating with little fuel and under unfavorable wind conditions show high variation in their nocturnal departure time. The latter may contain an unknown proportion of nocturnal movements not directly related to migratory flights. Excluding such movements is crucial to clearly identify the main drivers of the variation in nocturnal departure time. In general we assume that the observed variation in the nocturnal departure time is explained by individually different reactions norms of the innate migration program to both intrinsic and extrinsic factors.
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19.
  • Sié, Ali, et al. (författare)
  • The health and demographic surveillance system (HDSS) in Nouna, Burkina Faso, 1993-2007
  • 2010
  • Ingår i: Global Health Action. - 1654-9716 .- 1654-9880. ; 3
  • Tidskriftsartikel (refereegranskat)abstract
    • The Nouna Health and Demographic Surveillance System (HDSS) is located in rural Burkina Faso and has existed since 1992. Currently, it has about 78,000 inhabitants. It is a member of the International Network for the Demographic Evaluation of Populations and Their Health in Developing Countries (INDEPTH), a global network of members who conducts longitudinal health and demographic evaluation of populations in low- and middle-income countries. The health facilities consist of one hospital and 13 basic health centres (locally known as CSPS). The Nouna HDSS has been used as a sampling frame for numerous studies in the fields of clinical research, epidemiology, health economics, and health systems research. In this paper we review some of the main findings, and we describe the effects that almost 20 years of health research activities have shown in the population in general and in terms of the perception, economic implications, and other indicators. Longitudinal data analyses show that childhood, as well as overall mortality, has significantly decreased over the observation period 1993-2007. The under-five mortality rate dropped from about 40 per 1,000 person-years in the mid-1990s to below 30 per 1,000 in 2007. Further efforts are needed to meet goal four of the Millennium Development Goals, which is to reduce the under-five mortality rate by two-thirds between 1990 and 2015.
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20.
  • Teumer, Alexander, et al. (författare)
  • Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
  • 2019
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n =192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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  • Resultat 11-20 av 21
  • Föregående 1[2]3Nästa

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