Publications by authors named "Christine Wolf"

34 Publications

Disentangling multiple chemical and non-chemical stressors in a lotic ecosystem using a longitudinal approach.

Sci Total Environ 2021 May 25;769:144324. Epub 2020 Dec 25.

Helmholtz Centre for Environmental Research - UFZ, Department River Ecology, Brückstr. 3a, 39114 Magdeburg, Germany.

Meeting ecological and water quality standards in lotic ecosystems is often failed due to multiple stressors. However, disentangling stressor effects and identifying relevant stressor-effect-relationships in complex environmental settings remain major challenges. By combining state-of-the-art methods from ecotoxicology and aquatic ecosystem analysis, we aimed here to disentangle the effects of multiple chemical and non-chemical stressors along a longitudinal land use gradient in a third-order river in Germany. We distinguished and evaluated four dominant stressor categories along this gradient: (1) Hydromorphological alterations: Flow diversity and substrate diversity correlated with the EU-Water Framework Directive based indicators for the quality element macroinvertebrates, which deteriorated at the transition from near-natural reference sites to urban sites. (2) Elevated nutrient levels and eutrophication: Low to moderate nutrient concentrations together with complete canopy cover at the reference sites correlated with low densities of benthic algae (biofilms). We found no more systematic relation of algal density with nutrient concentrations at the downstream sites, suggesting that limiting concentrations are exceeded already at moderate nutrient concentrations and reduced shading by riparian vegetation. (3) Elevated organic matter levels: Wastewater treatment plants (WWTP) and stormwater drainage systems were the primary sources of bioavailable dissolved organic carbon. Consequently, planktonic bacterial production and especially extracellular enzyme activity increased downstream of those effluents showing local peaks. (4) Micropollutants and toxicity-related stress: WWTPs were the predominant source of toxic stress, resulting in a rapid increase of the toxicity for invertebrates and algae with only one order of magnitude below the acute toxic levels. This toxicity correlates negatively with the contribution of invertebrate species being sensitive towards pesticides (SPEAR index), probably contributing to the loss of biodiversity recorded in response to WWTP effluents. Our longitudinal approach highlights the potential of coordinated community efforts in supplementing established monitoring methods to tackle the complex phenomenon of multiple stress.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144324DOI Listing
May 2021

Action needed for the EU Common Agricultural Policy to address sustainability challenges.

People Nat (Hoboken) 2020 Jun 8;2(2):305-316. Epub 2020 Mar 8.

Thünen Institute for Rural Studies, Braunschweig, Germany.

Making agriculture sustainable is a global challenge. In the European Union (EU), the Common Agricultural Policy (CAP) is failing with respect to biodiversity, climate, soil, land degradation as well as socio-economic challenges.The European Commission's proposal for a CAP post-2020 provides a scope for enhanced sustainability. However, it also allows Member States to choose low-ambition implementation pathways. It therefore remains essential to address citizens' demands for sustainable agriculture and rectify systemic weaknesses in the CAP, using the full breadth of available scientific evidence and knowledge.Concerned about current attempts to dilute the environmental ambition of the future CAP, and the lack of concrete proposals for improving the CAP in the draft of the European Green Deal, we call on the European Parliament, Council and Commission to adopt 10 urgent action points for delivering sustainable food production, biodiversity conservation and climate mitigation.Knowledge is available to help moving towards evidence-based, sustainable European agriculture that can benefit people, nature and their joint futures.The statements made in this article have the broad support of the scientific community, as expressed by above 3,600 signatories to the preprint version of this manuscript. The list can be found here (https://doi.org/10.5281/zenodo.3685632).
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http://dx.doi.org/10.1002/pan3.10080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334041PMC
June 2020

Temporal Improvement of a COVID-19-Positive Crohn's Disease Patient Treated With Bismuth Subsalicylate.

Am J Gastroenterol 2020 08;115(8):1298

University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois, USA.

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http://dx.doi.org/10.14309/ajg.0000000000000725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302082PMC
August 2020

Janus kinase inhibition in complement component 1 deficiency.

J Allergy Clin Immunol 2020 12 20;146(6):1439-1442.e5. Epub 2020 Apr 20.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.002DOI Listing
December 2020

Aicardi-Goutières syndrome due to a paternal mosaic mutation.

Neurol Genet 2020 Feb 19;6(1):e384. Epub 2019 Dec 19.

Department of Pediatrics (V.T., C.W., N.L., M.A.L.-K.), Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden; Department of Neuropediatrics (M.D.-N., I.K.-M.), University of Tübingen, Germany; Child Neurology and Psychiatry Unit (M.S.), Paediatric Department, Bolzano Regional Hospital; Child Haematology and Oncology Unit (P.K.), Paediatric Department, Bolzano Regional Hospital, Italy; Institute of Medical Genetics and Applied Genomics (F.H.), University of Tübingen; and Center for Neurology and Hertie-Institute for Clinical Brain Research (J.R., R.S.), University of Tübingen and German Center of Neurodegenerative Diseases, Germany.

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http://dx.doi.org/10.1212/NXG.0000000000000384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936312PMC
February 2020

From Biology to Therapy: The CLL Success Story.

Hemasphere 2019 Apr 9;3(2):e175. Epub 2019 Feb 9.

Department of Internal Medicine III, Ulm University, Ulm, Germany.

Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia (CLL) over the last decade. Advances in monoclonal antibody technology have resulted in the development of newer generations of anti-CD20 antibodies with improved therapeutic effectiveness. In parallel, our knowledge about the distinctive biological characteristics of CLL has progressively deepened and has revealed the importance of B-cell receptor (BCR) signaling and upregulated antiapoptotic proteins for survival and expansion of malignant cell clones. This knowledge provided the basis for development of novel targeted agents that revolutionized treatment of CLL. Ibrutinib and idelalisib inhibit the Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) delta, respectively, thus interfering with supportive signals coming from the microenvironment via the BCR. These drugs induce egress of CLL cells from secondary lymphoid organs and remarkably improve clinical outcomes, especially for patients with unmutated immunoglobulin heavy-chain genes or with p53 abnormalities that do not benefit from classical treatment schemes. Latest clinical trial results have established ibrutinib with or without anti-CD20 antibodies as the preferred first-line treatment for most CLL patients, which will reduce the use of chemoimmunotherapy in the imminent future. Further advances are achieved with venetoclax, a BH3-mimetic that specifically inhibits the antiapoptotic B-cell lymphoma 2 protein and thus causes rapid apoptosis of CLL cells, which translates into deep and prolonged clinical responses including high rates of minimal residual disease negativity. This review summarizes recent advances in the development of targeted CLL therapies, including new combination schemes, novel BTK and PI3K inhibitors, spleen tyrosine kinase inhibitors, immunomodulatory drugs, and cellular immunotherapy.
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http://dx.doi.org/10.1097/HS9.0000000000000175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746030PMC
April 2019

The WW1 Domain Enhances Autoinhibition in Smurf Ubiquitin Ligases.

J Mol Biol 2019 12 16;431(24):4834-4847. Epub 2019 Oct 16.

Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, 72076 Tübingen, Germany; Institute of Biophysics and Physical Biochemistry, University of Regensburg, Universitätsstr. 31, 93040 Regensburg, Germany. Electronic address:

Downregulation of ubiquitin (Ub) ligase activity prevents premature ubiquitination and is critical for cellular homeostasis. Nedd4 Ub ligases share a common domain architecture and yet are regulated in distinct ways through interactions of the catalytic HECT domain with the N-terminal C2 domain or the central WW domain region. Smurf1 and Smurf2 are two highly related Nedd4 ligases with ~70% overall sequence identity. Here, we show that the Smurf1 C2 domain interacts with the HECT domain and inhibits ligase activity in trans. However, in contrast to Smurf2, we find that full-length Smurf1 is a highly active Ub ligase, and we can attribute this striking difference in regulation to the lack of one WW domain (WW1) in Smurf1. Using NMR spectroscopy and biochemical assays, we identified the WW1 region as an additional inhibitory element in Smurf2 that cooperates with the C2 domain to enhance HECT domain binding and Smurf2 inhibition. Our work provides important insights into Smurf regulation and highlights that the activities of highly related proteins can be controlled in distinct ways.
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http://dx.doi.org/10.1016/j.jmb.2019.09.018DOI Listing
December 2019

Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3.

J Exp Med 2019 07 24;216(7):1700-1723. Epub 2019 May 24.

Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-κB signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed -deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell-specific deletions of to demonstrate that Regnase-3 acts specifically within myeloid cells. deficiency systemically increased IFN signaling, which increased the proportion of immature B and innate immune cells, and suppressed follicle and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Unlike Regnase-1, Regnase-3 expression is high specifically in macrophages and is transcriptionally controlled by IFN signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade, and regulate mRNAs, such as (), in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase essential for immune homeostasis but has diverged as key regulator in the IFN pathway in macrophages.
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http://dx.doi.org/10.1084/jem.20181762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605757PMC
July 2019

Assessment of Clinical Response to Janus Kinase Inhibition in Patients With Familial Chilblain Lupus and TREX1 Mutation.

JAMA Dermatol 2019 03;155(3):342-346

Department of Dermatology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany.

Importance: Familial chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). Familial chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available.

Objectives: To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial chilblain lupus and assess the effect of cold on patient fibroblasts.

Design, Setting, And Participants: In this case series, 3 patients with familial chilblain lupus due to TREX1 mutation underwent treatment with baricitinib for 3 months.

Interventions: Doses of baricitinib, 4 mg, were administered daily for 3 months.

Main Outcomes And Measures: Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed.

Results: All 3 patients (2 women and 1 man; mean [SD] age, 51 [24] years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro.

Conclusions And Relevance: These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold in TREX1-deficient cells. This finding may be relevant to other type I IFN-mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.
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http://dx.doi.org/10.1001/jamadermatol.2018.5077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440279PMC
March 2019

Complications in Pediatric Regional Anesthesia: An Analysis of More than 100,000 Blocks from the Pediatric Regional Anesthesia Network.

Anesthesiology 2018 10;129(4):721-732

From the Departments of Anesthesiology (B.J.W.) Biostatistics and Medical Informatics (J.B.), University of Wisconsin School of Medicine and Public Health, American Family Children's Hospital, Madison, Wisconsin the Department of Anesthesiology, Emory University School of Medicine, Children's Healthcare of Atlanta at Egleston Children's Hospital, Atlanta, Georgia ( J.B.L.) the Department of Anesthesiology, University of Mississippi Medical Center, Jackson, Mississippi (M.S.) Axio Research LLC, Seattle, Washington (C.W.) the Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, Washington (A.T.B., S.H.F.) the Departments of Pediatrics and Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, Lucile Packard Children's Hospital, Palo Alto, California (E.J.K.) the Department of Anesthesiology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts (N.F.S.) the Department of Pediatric Anesthesiology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois (S.S.) the Departments of Anesthesiology and Pediatrics, Dartmouth Medical School, Children's Hospital at Dartmouth, Lebanon, New Hampshire (A.H.T.) the Departments of Anesthesiology and Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado (D.M.P.). Seattle Children's Hospital Seattle Children's Hospital Seattle Children's Hospital Seattle Children's Hospital Seattle Children's Hospital Seattle Children's Hospital Lurie Children's Hospital, Northwestern University Lurie Children's Hospital, Northwestern University Lurie Children's Hospital, Northwestern University Lucile Packard Children's Hospital at Stanford Children's Medical Center, Dallas Children's Medical Center, Dallas The Cleveland Clinic Boston Children's Hospital University of Texas, Houston University of Texas, Houston University of New Mexico University of New Mexico Texas Children's Hospital Texas Children's Hospital Texas Children's Hospital Texas Children's Hospital Doernbecher Children's Hospital, Oregon Health Sciences University Amplatz Children's Hospital/University of Minnesota Amplatz Children's Hospital/University of Minnesota Riley Hospital for Children at Indiana University Health Riley Hospital for Children at Indiana University Health Hospital for Special Surgery, New York Hospital for Special Surgery, New York Children's Healthcare of Atlanta at Egleston Children's Hospital, Emory University Children's Healthcare of Atlanta at Egleston Children's Hospital, Emory University Children's of Mississippi, University of Mississippi Joe DiMaggio Children's Hospital Columbia University University Hospital Rijeka, Croatia Nationwide Children's Hospital, Ohio State University Hospital Municipal Jesus, Rio De Janiero, Brazil Selçuk University, Konya, Turkey Monroe Carrell Children's Hospital, Vanderbilt University Wellstar Medical Group Children's National Medical Center Children's National Medical Center Massachusetts General Hospital for Children Massachusetts General Hospital for Children.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children's hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children.

Methods: This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy.

Results: There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%).

Conclusions: The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.
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http://dx.doi.org/10.1097/ALN.0000000000002372DOI Listing
October 2018

Therapeutic Approaches to Type I Interferonopathies.

Curr Rheumatol Rep 2018 04 20;20(6):32. Epub 2018 Apr 20.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

Purpose Of Review: To review recent scientific advances and therapeutic approaches in the expanding field of type I interferonopathies. Type I interferonopathies represent a genetically and phenotypically heterogenous group of disorders of the innate immune system caused by constitutive activation of antiviral type I interferon (IFN). Clinically, type I interferonopathies are characterized by autoinflammation and varying degrees of autoimmunity or immunodeficiency. The elucidation of the underlying genetic causes has revealed novel cell-intrinsic mechanisms that protect the organism against inappropriate immune recognition of self nucleic acids by cytosolic nucleic acid sensors. The type I IFN system is subject to a tight and complex regulation. Disturbances of its checks and balances can spark an unwanted immune response causing uncontrolled type I IFN signaling. Novel mechanistic insight into pathways that control the type I IFN system is providing opportunities for targeted therapeutic approaches by repurposing drugs such as Janus kinase inhibitors or reverse transcriptase inhibitors.
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http://dx.doi.org/10.1007/s11926-018-0743-3DOI Listing
April 2018

Variable clinical phenotype in two siblings with Aicardi-Goutières syndrome type 6 and a novel mutation in the ADAR gene.

Eur J Paediatr Neurol 2018 Jan 22;22(1):186-189. Epub 2017 Nov 22.

Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Electronic address:

Aicardi-Goutières syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings.
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http://dx.doi.org/10.1016/j.ejpn.2017.11.003DOI Listing
January 2018

Single Cell Gel Electrophoresis for the Detection of Genomic Ribonucleotides.

Methods Mol Biol 2018 ;1672:311-318

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

Single cell gel electrophoresis or comet assay enables the quantification of DNA damage such as single-strand or double-strand breaks on a single cell level. Here, we describe a variant of this method for the detection of ribonucleotides embedded in genomic DNA. Briefly, cells are embedded in agarose on a microscopic slide, lysed under high salt and alkaline conditions and then subjected to in situ treatment with E. coli RNase HII which nicks 5' to a ribonucleotide within the context of a DNA duplex thereby converting genomic ribonucleotides into strand breaks. After unwinding of genomic DNA using a highly alkaline buffer, electrophoresis under mild alkaline conditions is performed resulting in formation of comets due to migration of fragmented DNA toward the anode. Following SYBR Gold staining comets can be visualized by fluorescence microscopy. In this setting, the length and the intensity of comets formed reflect the level of genomic ribonucleotides present in a given cell.
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http://dx.doi.org/10.1007/978-1-4939-7306-4_21DOI Listing
June 2018

NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib.

Int J Cancer 2018 01 9;142(2):322-333. Epub 2017 Oct 9.

Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.

B cell receptor (BCR) signaling is a key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. To detect novel candidate therapeutic targets, we performed a genome-wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2,192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL. Intriguingly, NFATC1 promoter DNA hypomethylation levels were significantly variant in clinical trial cohorts from different disease progression stages and furthermore correlated with Binet disease staging and thymidine kinase levels, strongly suggesting a central role of NFATC1 in CLL development. Functionally, DNA hypomethylation at NFATC1 promoter inversely correlated with RNA levels of NFATC1 and dysregulation correlated with expression of target genes BCL-2, CCND1 and CCR7. The inhibition of the NFAT regulator calcineurin with tacrolimus and cyclosporin A and the BCR signaling inhibitor ibrutinib significantly reduced NFAT activity in leukemic cell lines, and NFAT inhibition resulted in increased apoptosis of primary CLL cells. In summary, our results indicate that the aberrant activation of NFATC1 by DNA hypomethylation and BCR signaling plays a major role in the pathomechanism of CLL.
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http://dx.doi.org/10.1002/ijc.31057DOI Listing
January 2018

Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis.

Nat Commun 2017 04 28;8:15069. Epub 2017 Apr 28.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Obere Zahlbarer Str 67, 55131 Mainz, Germany.

Bcl-3 is an atypical NF-κB family member that regulates NF-κB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the infiltration of immune cells such as pro-inflammatory γδT cells, but not αβ T cells. In Treg cells, Bcl-3 associates directly with NF-κB p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-κB dimers, thereby regulating NF-κB-mediated gene expression. This study thus reveals intrinsic functions of Bcl-3 in Treg cells, identifies Bcl-3 as a potential prognostic marker for colitis and illustrates the mechanism by which Bcl-3 regulates NF-κB activity in Tregs to prevent colitis.
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http://dx.doi.org/10.1038/ncomms15069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414353PMC
April 2017

Water Quality Is a Poor Predictor of Recreational Hotspots in England.

PLoS One 2016 22;11(11):e0166950. Epub 2016 Nov 22.

UFZ, Helmholtz Centre for Environmental Research, Department of Computational Landscape Ecology, Permoserstraße 15, 04318 Leipzig, Germany.

Maintaining and improving water quality is key to the protection and restoration of aquatic ecosystems, which provide important benefits to society. In Europe, the Water Framework Directive (WFD) defines water quality based on a set of biological, hydro-morphological and chemical targets, and aims to reach good quality conditions in all river bodies by the year 2027. While recently it has been argued that achieving these goals will deliver and enhance ecosystem services, in particular recreational services, there is little empirical evidence demonstrating so. Here we test the hypothesis that good water quality is associated with increased utilization of recreational services, combining four surveys covering walking, boating, fishing and swimming visits, together with water quality data for all water bodies in eight River Basin Districts (RBDs) in England. We compared the percentage of visits in areas of good water quality to a set of null models accounting for population density, income, age distribution, travel distance, public access, and substitutability. We expect such association to be positive, at least for fishing (which relies on fish stocks) and swimming (with direct contact to water). We also test if these services have stronger association with water quality relative to boating and walking alongside rivers, canals or lakeshores. In only two of eight RBDs (Northumbria and Anglian) were both criteria met (positive association, strongest for fishing and swimming) when comparing to at least one of the null models. This conclusion is robust to variations in dataset size. Our study suggests that achieving the WFD water quality goals may not enhance recreational ecosystem services, and calls for further empirical research on the connection between water quality and ecosystem services.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119820PMC
June 2017

Familial chilblain lupus due to a gain-of-function mutation in STING.

Ann Rheum Dis 2017 Feb 26;76(2):468-472. Epub 2016 Aug 26.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Objectives: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology.

Methods: Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-β reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes.

Results: In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature.

Conclusions: A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.
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http://dx.doi.org/10.1136/annrheumdis-2016-209841DOI Listing
February 2017

RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA.

Nat Commun 2016 05 27;7:11752. Epub 2016 May 27.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

Immune recognition of cytosolic DNA represents a central antiviral defence mechanism. Within the host, short single-stranded DNA (ssDNA) continuously arises during the repair of DNA damage induced by endogenous and environmental genotoxic stress. Here we show that short ssDNA traverses the nuclear membrane, but is drawn into the nucleus by binding to the DNA replication and repair factors RPA and Rad51. Knockdown of RPA and Rad51 enhances cytosolic leakage of ssDNA resulting in cGAS-dependent type I IFN activation. Mutations in the exonuclease TREX1 cause type I IFN-dependent autoinflammation and autoimmunity. We demonstrate that TREX1 is anchored within the outer nuclear membrane to ensure immediate degradation of ssDNA leaking into the cytosol. In TREX1-deficient fibroblasts, accumulating ssDNA causes exhaustion of RPA and Rad51 resulting in replication stress and activation of p53 and type I IFN. Thus, the ssDNA-binding capacity of RPA and Rad51 constitutes a cell intrinsic mechanism to protect the cytosol from self DNA.
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http://dx.doi.org/10.1038/ncomms11752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895045PMC
May 2016

Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene.

Pediatr Rheumatol Online J 2015 Sep 7;13(1):37. Epub 2015 Sep 7.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia.
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http://dx.doi.org/10.1186/s12969-015-0035-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562156PMC
September 2015

Type I interferonopathies--an expanding disease spectrum of immunodysregulation.

Semin Immunopathol 2015 Jul 22;37(4):349-57. Epub 2015 May 22.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany,

Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN signaling is activated by pattern recognition receptors upon sensing of viral nucleic acids and induces antiviral programs through modulation of innate and adaptive immune responses. Type I interferonopathies comprise a heterogenous group of genetically determined diseases that are characterized by inappropriate activation of type I IFN. While their phenotypic spectrum is broad, ranging from severe neurological impairment to mild cutaneous disease, systemic autoinflammation, and autoimmunity are commonly shared signs of type I interferonopathies. Although the mechanisms underlying various disease phenotypes associated with inappropriate type I IFN activation have yet to be fully elucidated, our current understanding of the molecular pathogenesis of type I interferonopathies has provided a set of candidate molecules that can be interrogated in search of targeted therapies.
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http://dx.doi.org/10.1007/s00281-015-0500-xDOI Listing
July 2015

Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1).

JAMA Dermatol 2015 Apr;151(4):426-31

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Importance: Familial chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial chilblain lupus is usually caused by a mutation in TREX1 (3' repair exonuclease 1).

Observations: We report on a family with dominant chilblain lupus segregating a novel TREX1 mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain. Affected family members experienced cold-induced chilblain lesions of varying degrees, ranging from bluish-red infiltrations to mutilating necrotic ulcerations. In addition, all patients showed signs of systemic disease, such as arthritis, lymphopenia, or antinuclear antibodies. An increased expression of myxovirus resistance protein A in the skin and induction of interferon-stimulated genes in peripheral blood cells demonstrated activation of type I interferon.

Conclusions And Relevance: This case further implicates type I interferon-dependent innate immune activation in the pathogenesis of TREX1-associated familial chilblain lupus. Unlike previously reported TREX1 mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial chilblain lupus.
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http://dx.doi.org/10.1001/jamadermatol.2014.3438DOI Listing
April 2015

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.

J Clin Invest 2015 Jan 15;125(1):413-24. Epub 2014 Dec 15.

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.
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http://dx.doi.org/10.1172/JCI78001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382239PMC
January 2015

Side effects from use of one or more psychiatric medications in a population-based sample of children and adolescents.

J Child Adolesc Psychopharmacol 2014 Mar 7;24(2):83-9. Epub 2014 Feb 7.

1 Department of Psychiatry, Seattle Children's/University of Washington , Seattle, Washington.

Objective: The purpose of this study was to investigate the side effect risks from using one or more psychiatric medications (including antipsychotics, antidepressants, α-2 agonists, benzodiazepines, mood stabilizers, and stimulants) among a national cohort of children and adolescents.

Methods: A questionnaire survey was administered to parents who filled a prescription for a psychiatric medication for their child at a large national retail pharmacy chain. Primary outcome variables were the total count of side effects from a list of 12 problem areas, as well as parent-reported side effect intensity (mild/moderate/severe). Modifiers investigated included specific medication and number of medications utilized, demographics, and difficulties with access to care.

Results: A total of 1347 parents of study subjects ages 3-17 years from 30 U.S. states who were taking psychiatric medications for any indication purchased at one retail pharmacy chain enrolled following a single mail invitation (7.5% response). Of the study subjects, 80% were white/non-Hispanic, 64% were male, 63% had private health insurance, and 67% had used a current medication for >1year. Most (84%) had one or more parent-reported side effect. After adjusting for covariates, subjects with two medications reported 17% (p<0.001) and with three or more medications reported 38% (p=0.002) increases in their average number of side effects than did children taking one medication. Parental reporting of difficulties in accessing care also predicted a 42% (p<0.001) greater number of side effects than for those who had no access difficulties. Side effects were particularly more common in medication combinations including either selective serotonin reuptake inhibitors (SSRIs) (77% higher odds, p<0.001) or antipsychotics (99% higher odds, p<0.001).

Conclusions: Side effects from psychiatric medications appear to be both more common and more severe overall with increasing numbers of medications utilized, and with perceived difficulty in accessing care. Polypharmacy regimens including either SSRIs or antipsychotics were especially associated with experiencing side effects, within this study sample.
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http://dx.doi.org/10.1089/cap.2013.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967377PMC
March 2014

SAMHD1 prevents autoimmunity by maintaining genome stability.

Ann Rheum Dis 2015 Mar 20;74(3):e17. Epub 2014 Jan 20.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Objectives: The HIV restriction factor, SAMHD1 (SAM domain and HD domain-containing protein 1), is a triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs). Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), an inflammatory disorder that shares phenotypic similarity with systemic lupus erythematosus, including activation of antiviral type 1 interferon (IFN). To further define the pathomechanisms underlying autoimmunity in AGS due to SAMHD1 mutations, we investigated the physiological properties of SAMHD1.

Methods: Primary patient fibroblasts were examined for dNTP levels, proliferation, senescence, cell cycle progression and DNA damage. Genome-wide transcriptional profiles were generated by RNA sequencing. Interaction of SAMHD1 with cyclin A was assessed by coimmunoprecipitation and fluorescence cross-correlation spectroscopy. Cell cycle-dependent phosphorylation of SAMHD1 was examined in synchronised HeLa cells and using recombinant SAMHD1. SAMHD1 was knocked down by RNA interference.

Results: We show that increased dNTP pools due to SAMHD1 deficiency cause genome instability in fibroblasts of patients with AGS. Constitutive DNA damage signalling is associated with cell cycle delay, cellular senescence, and upregulation of IFN-stimulated genes. SAMHD1 is phosphorylated by cyclin A/cyclin-dependent kinase 1 in a cell cycle-dependent manner, and its level fluctuates during the cell cycle, with the lowest levels observed in G1/S phase. Knockdown of SAMHD1 by RNA interference recapitulates activation of DNA damage signalling and type 1 IFN activation.

Conclusions: SAMHD1 is required for genome integrity by maintaining balanced dNTP pools. dNTP imbalances due to SAMHD1 deficiency cause DNA damage, leading to intrinsic activation of IFN signalling. These findings establish a novel link between DNA damage signalling and innate immune activation in the pathogenesis of autoimmunity.
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http://dx.doi.org/10.1136/annrheumdis-2013-204845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345975PMC
March 2015

Community child psychiatric medication experiences measured by an internet-based, prospective parent survey of retail pharmacy customers.

Community Ment Health J 2014 Feb 10;50(2):172-8. Epub 2013 Dec 10.

Department of Psychiatry and Behavioral Health, Seattle Children's Hospital, University of Washington, M/S CPH, 4800 Sand Point Way NE, Seattle, WA, 98145, USA,

One thousand five hundred parents filling a psychiatric prescription for their 6-18 year old child with a multi-state retail pharmacy chain received a single mailed invitation to complete a detailed online survey. 276 parents responded (18.4%). 60% of children on medications had a parent rated CBCL scale score in the clinically significant range at enrollment (T score ≥65), with a similar frequency of clinically significant CBCL scores through 15 months of survey followup. 47% of medication regimens were noted to be causing persistent side effects. This simple community based data collection method can offer a unique way to investigate naturalistic treatment outcomes.
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http://dx.doi.org/10.1007/s10597-013-9671-xDOI Listing
February 2014

Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay.

Nat Struct Mol Biol 2013 Jan 2;20(1):73-81. Epub 2012 Dec 2.

Institute of Molecular Immunology, Helmholtz Zentrum München, München, Germany.

The exoRNase Eri1 inhibits RNA interference and trims the 5.8S rRNA 3' end. It also binds to the stem-loop of histone mRNAs, but the functional importance of this interaction remains elusive. Histone mRNAs are normally degraded at the end of S phase or after pharmacological inhibition of replication. Both processes are impaired in Eri1-deficient mouse cells, which instead accumulate oligouridylated histone mRNAs. Eri1 trims the mature histone mRNAs by two unpaired nucleotides at the 3' end but stalls close to the double-stranded stem. Upon oligouridylation of the histone mRNA, the Lsm1-7 heteroheptamer recognizes the oligo(U) tail and interacts with Eri1, whose catalytic activity is then able to degrade the stem-loop in a stepwise manner. These data demonstrate how degradation of histone mRNAs is initiated when 3' oligouridylation creates a cis element that enables Eri1 to process the double-stranded stem-loop structure.
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http://dx.doi.org/10.1038/nsmb.2450DOI Listing
January 2013

Pediatric Regional Anesthesia Network (PRAN): a multi-institutional study of the use and incidence of complications of pediatric regional anesthesia.

Anesth Analg 2012 Dec 13;115(6):1353-64. Epub 2012 Jun 13.

Departments of Anesthesiology and Pediatrics, Children's Hospital Colorado, 13123 East 16th Ave., B090, Aurora, CO 80045, USA.

Background: Regional anesthesia is increasingly used in pediatric patients to provide postoperative analgesia and to supplement intraoperative anesthesia. The Pediatric Regional Anesthesia Network was formed to obtain highly audited data on practice patterns and complications and to facilitate collaborative research in regional anesthetic techniques in infants and children.

Methods: We constructed a centralized database to collect detailed prospective data on all regional anesthetics performed by anesthesiologists at the participating centers. Data were uploaded via a secure Internet connection to a central server. Data were rigorously audited for accuracy and errors were corrected. All anesthetic records were scrutinized to ensure that every block that was performed was captured in the database. Intraoperative and postoperative complications were tracked until their resolution. Blocks were categorized by type and as single-injection or catheter (continuous) blocks.

Results: A total of 14,917 regional blocks, performed on 13,725 patients, were accrued from April 1, 2007 through March 31, 2010. There were no deaths or complications with sequelae lasting >3 months (95% CI 0-2:10,000). Single-injection blocks had fewer adverse events than continuous blocks, although the most frequent events (33% of all events) in the latter group were catheter-related problems. Ninety-five percent of blocks were placed while patients were under general anesthesia. Single-injection caudal blocks were the most frequently performed (40%), but peripheral nerve blocks were also frequently used (35%), possibly driven by the widespread use of ultrasound (83% of upper extremity and 69% of lower extremity blocks).

Conclusions: Regional anesthesia in children as commonly performed in the United States has a very low rate of complications, comparable to that seen in the large multicenter European studies. Ultrasound may be increasing the use of peripheral nerve blocks. Multicenter collaborative networks such as the Pediatric Regional Anesthesia Network can facilitate the collection of detailed prospective data for research and quality improvement.
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http://dx.doi.org/10.1213/ANE.0b013e31825d9f4bDOI Listing
December 2012

Characterization of the self-cleaving effector protein NopE1 of Bradyrhizobium japonicum.

J Bacteriol 2011 Aug 3;193(15):3733-9. Epub 2011 Jun 3.

Institute of Genetics, Dresden University of Technology, 01062 Dresden, Germany.

NopE1 is a type III-secreted protein of the symbiont Bradyrhizobium japonicum which is expressed in nodules. In vitro it exhibits self-cleavage in a duplicated domain of unknown function (DUF1521) but only in the presence of calcium. Here we show that either domain is self-sufficient for cleavage. An exchange of the aspartic acid residue at the cleavage site with asparagine prevented cleavage; however, cleavage was still observed with glutamic acid at the same position, indicating that a negative charge at the cleavage site is sufficient. Close to each cleavage site, an EF-hand-like motif is present. A replacement of one of the conserved aspartic acid residues with alanine prevented cleavage at the neighboring site. Except for EDTA, none of several protease inhibitors blocked cleavage, suggesting that a known protease-like mechanism is not involved in the reaction. In line with this, the reaction takes place within a broad pH and temperature range. Interestingly, magnesium, manganese, and several other divalent cations did not induce cleavage, indicating a highly specific calcium-binding site. Based on results obtained by blue-native gel electrophoresis, it is likely that the uncleaved protein forms a dimer and that the fragments of the cleaved protein oligomerize. A database search reveals that the DUF1521 domain is present in proteins encoded by Burkholderia phytofirmans PsNJ (a plant growth-promoting betaproteobacterium) and Vibrio coralliilyticus ATCC BAA450 (a pathogenic gammaproteobacterium). Obviously, this domain is more widespread in proteobacteria, and it might contribute to the interaction with hosts.
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http://dx.doi.org/10.1128/JB.00437-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147523PMC
August 2011