467 results on '"Spengler D"'
Search Results
152. The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas
- Author
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Pagotto U, Arzberger T, Theodoropoulou M, Grübler Y, Pantaloni C, Saeger W, Losa M, Laurent Journot, Gk, Stalla, and Spengler D
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Adenoma ,DNA, Complementary ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Suppressor Proteins ,Blotting, Western ,Cell Cycle Proteins ,Zinc Fingers ,Oligonucleotides, Antisense ,Immunohistochemistry ,ErbB Receptors ,Pituitary Gland ,Mutation ,Trans-Activators ,Humans ,Genes, Tumor Suppressor ,Pituitary Neoplasms ,RNA, Messenger ,Cell Division ,In Situ Hybridization ,Transcription Factors - Abstract
The ZAC gene encodes a new zinc-finger protein that concomitantly induces apoptosis and cell cycle arrest and localizes to chromosome 6q24-q25, a well-known hot spot related to cancer. ZAC is highly expressed in the anterior pituitary gland, and its ablation by antisense targeting promotes pituitary cell proliferation. Here we investigate ZAC status in pituitary tumors to evaluate its role in pituitary tumorigenesis. Interest ingly, a strong reduction or absence of ZAC mRNA and protein expres sion was detected in nonfunctioning pituitary adenomas, whereas in clin ically active pituitary neoplasias, the decrease in ZAC expression was variable. Loss of expression was not associated with a mutation of the ZAC gene. Our observations suggest that alternative mechanisms of gene inactivation and/or altered regulation of the ZAC gene occur in nonfunctioning pituitary adenomas.
153. Isometric strength testing. Recommendations based on a statistical analysis of the procedure
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Zeh J, Hansson T, Bigos S, Spengler D, Michele Battié, and Wortley M
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Male ,Risk ,Back Pain ,Isometric Contraction ,Back Injuries ,Exercise Test ,Humans ,Female ,Muscle Contraction - Abstract
Back injuries occurring during isometric strength testing motivated a statistical analysis to determine if a reduction in the number of exertions during the test was possible without profound influence upon the accuracy of the results. Strength measurements from more than 1,000 volunteers in an industrial back pain study were examined. It was concluded that one exertion in each test position for each subject provided a reasonably good indication of the subject's strength in that position, but strength in one position.
154. Correction of BRDF-effects in vegetation indices using simulated Sentinel-2 data
- Author
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Theres Kuester, Segl, K., Spengler, D., and Kaufmann, H.
- Subjects
550 - Earth sciences
155. B-scan ultrasonic measurement of the lumbar spinal canal as a predictor of industrial back pain complaints and extended work loss
- Author
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Michele Battié, Hansson T, Bigos S, Zeh J, Fisher L, and Spengler D
- Subjects
Adult ,Male ,Lumbar Vertebrae ,Work Capacity Evaluation ,Middle Aged ,Spinal Stenosis ,Risk Factors ,Absenteeism ,Multivariate Analysis ,Humans ,Female ,Low Back Pain ,Aged ,Ultrasonography - Abstract
B-scan ultrasonic measurements of lumbar spinal canal diameter were examined as predictors of industrial back pain complaints and extended work loss. Baseline data were collected on 3,020 Washington State aircraft manufacturing workers, and over a mean 3.7-year follow-up period 352 subjects reported industrial back pain complaints. Mean canal measurements of subjects with industrial back pain complaints were smaller at all spinal levels than in subjects without complaints. The mean differences between the groups, however, were extremely small (0.07 mm to 0.51 mm), and not all levels were statistically significant. The relative risk for an L5-S1 measurement 2 standard deviations below the mean was 1.4, yet the measurement explained less than 1% of the uncertainty in predicting complaints. No association was found between canal measurements and claims with extended work loss of greater than one month. The imprecision of the measurements and poor predictive ability indicate that B-scan ultrasonography, as used in this study, is of dubious screening value.
156. Fixation of porous titanium implants in cortical bone enhanced by electrical stimulation
- Author
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Colella, S. M., primary, Miller, A. G., additional, Stang, R. G., additional, Stoebe, T. G., additional, and Spengler, D. M., additional
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- 1981
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157. Chronic low back pain
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Addison, R. G., primary, Loeser, J., additional, Spengler, D., additional, and Fordyce, W., additional
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- 1984
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158. Effects of Spaceflight on Structural and Material Strength of Growing Bone
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Spengler, D. M., primary, Morey, E. R., additional, Carter, D. R., additional, Turner, R. T., additional, and Baylink, D. J., additional
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- 1983
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159. Effects of doxepin and desipramine on chronic, back pain with depression
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Ward, N. G., primary, Bokan, J., additional, Phillips, M., additional, Benedetti, C., additional, Butler, S., additional, Spengler, D., additional, and Kigos, S., additional
- Published
- 1984
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160. Epiphyseal Plate Shear Strength in Rats Treated with a Diphosphonate
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Spengler, D. M., primary, Evans, R., additional, Baylink, D. J., additional, and Spolek, G. A., additional
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- 1980
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161. The Effect of Aminopropionitrile (BAPN) on Bone Mineralization
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Rosenquist, J. B., primary, Baylink, D. J., additional, and Spengler, D. M., additional
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- 1977
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162. Trennung und bestimmung von carbamat- und harnstoffherbiziden durch reaktions-gaschromatographie
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Spengler, D., primary and Hamroll, B., additional
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- 1970
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163. Simultaneous DNA and RNA isolation from brain punches for epigenetics
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Bettscheider, M, Murgatroyd, C, and Spengler, D
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Medicine(all) ,lcsh:Biology (General) ,Biochemistry, Genetics and Molecular Biology(all) ,lcsh:R ,Technical Note ,lcsh:Medicine ,lcsh:Science (General) ,lcsh:QH301-705.5 ,lcsh:Q1-390 - Abstract
Background Epigenetic modifications such as DNA methylation play an important role for gene expression and are regulated by developmental and environmental signals. DNA methylation typically occurs in a highly tissue- and cell-specific manner. This raises a severe challenge when studying discrete, small regions of the brain where cellular heterogeneity is high and tissue quantity limited. Because gene expression and methylation are often tightly linked it appears of interest to compare both parameters in the same sample. Findings We present a refined method for the simultaneous extraction of DNA for bisulfite sequencing and RNA for expression analysis from small mouse brain tissue punches. This method can also be easily adapted for other small tissues or cell populations. Conclusions The method described herein results in DNA and RNA of a quantity and quality permitting highly reliable bisulfite analysis and quantitative RT-PCR measurements, respectively.
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164. Simultaneous DNA and RNA isolation from brain punches for epigenetics
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Spengler Dietmar, Murgatroyd Chris, and Bettscheider Marc
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Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Background Epigenetic modifications such as DNA methylation play an important role for gene expression and are regulated by developmental and environmental signals. DNA methylation typically occurs in a highly tissue- and cell-specific manner. This raises a severe challenge when studying discrete, small regions of the brain where cellular heterogeneity is high and tissue quantity limited. Because gene expression and methylation are often tightly linked it appears of interest to compare both parameters in the same sample. Findings We present a refined method for the simultaneous extraction of DNA for bisulfite sequencing and RNA for expression analysis from small mouse brain tissue punches. This method can also be easily adapted for other small tissues or cell populations. Conclusions The method described herein results in DNA and RNA of a quantity and quality permitting highly reliable bisulfite analysis and quantitative RT-PCR measurements, respectively.
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- 2011
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165. Atomic-beam spectroscopy of [formula omitted] levels ( n=7, 8) in 203,205Tl
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Hermann, G., Lasnitschka, G., Scharmann, A., and Spengler, D.
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- 1990
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166. Functional properties of deoxycorticosterone and spironolactone: molecular characterization and effects on sleep-endocrine activity
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Steiger, A., Rupprecht, R., Spengler, D., and Guldner, J.
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- 1993
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167. Effects of specimen load-bearing and free surface layers on the compressive mechanical properties of cellular materials
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Zhu, M., Keller, T. S., and Spengler, D. M.
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- 1994
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168. Interpretation and parameterization of dynamic trunk isoinertial movements using an ensemble-averaging technique
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Keller, T. S., Szpalski, M., Spengler, D. M., and Hayez, J. P.
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- 1993
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169. Multiplanar Variations in the Structural Characteristics of Cancellous Bone
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Zhu, M., Keller, T. S., Moeljanto, E., and Spengler, D. M.
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- 1994
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170. Hyperfine structures and isotope shifts of the CuD~1 and D~2 lines measured by high-resolution laser fluorescence spectroscopy with a collimated atomic beam
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Hermann, G., Lasnitschka, G., Schwabe, C., and Spengler, D.
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- 1993
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171. Epigenetic Biomarkers of Prenatal Maternal Stress
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Serpeloni, Fernanda, Radtke, Karl M., Hecker, Tobias, Elbert, Thomas, Spengler, Dietmar, Wetzel, Elisabeth, University of Zurich, Spengler, D, and Binder, Elisabeth B
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0301 basic medicine ,Candidate gene ,Pregnancy ,10093 Institute of Psychology ,business.industry ,Offspring ,Social environment ,Bioinformatics ,medicine.disease ,Mental health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Prenatal stress ,DNA methylation ,Medicine ,Epigenetics ,150 Psychology ,business ,030217 neurology & neurosurgery - Abstract
Diverse maternal experiences or mood disturbances before birth pose a substantial risk for poor lifetime mental health outcomes. DNA methylation variation in response to prenatal stress has been shown in animal model studies. Although prenatal time represents a sensitive period of development, little is known about the impact of maternal stress during pregnancy on DNA methylation during the life span in humans. In this review, we provide a brief summary of key human studies that bring evidence of DNA methylation in association with prenatal stress. We discuss common findings in the studies such as the type of maternal stress associated to offspring’s DNA methylation and plasticity/stability of epigenetic variations. We also suggest the contribution of additional candidate gene approaches and genome-wide DNA methylation profile, in order to further explore and define the relationship between early social environment, epigenetics, and long-term outcomes. The implications of maternal care on DNA methylation as well as the importance of maternal well-being during pregnancy to prevent future health problems are considered.
- Published
- 2016
172. Peripheral immune cell-derived matrix metalloprotease 8 (MMP8): brain trafficking promotes depression-like behavior.
- Author
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Spengler D and Rein T
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- Animals, Mice, Humans, Depression immunology, Depression genetics, Depression pathology, Brain immunology, Brain metabolism
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- 2024
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173. Polygenic risk for schizophrenia converges on alternative polyadenylation as molecular mechanism underlying synaptic impairment.
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Raabe FJ, Hausruckinger A, Gagliardi M, Ahmad R, Almeida V, Galinski S, Hoffmann A, Weigert L, Rummel CK, Murek V, Trastulla L, Jimenez-Barron L, Atella A, Maidl S, Menegaz D, Hauger B, Wagner EM, Gabellini N, Kauschat B, Riccardo S, Cesana M, Papiol S, Sportelli V, Rex-Haffner M, Stolte SJ, Wehr MC, Salcedo TO, Papazova I, Detera-Wadleigh S, McMahon FJ, Schmitt A, Falkai P, Hasan A, Cacchiarelli D, Dannlowski U, Nenadić I, Kircher T, Scheuss V, Eder M, Binder EB, Spengler D, Rossner MJ, and Ziller MJ
- Abstract
Schizophrenia (SCZ) is a genetically heterogenous psychiatric disorder of highly polygenic nature. Correlative evidence from genetic studies indicate that the aggregated effects of distinct genetic risk factor combinations found in each patient converge onto common molecular mechanisms. To prove this on a functional level, we employed a reductionistic cellular model system for polygenic risk by differentiating induced pluripotent stem cells (iPSCs) from 104 individuals with high polygenic risk load and controls into cortical glutamatergic neurons (iNs). Multi-omics profiling identified widespread differences in alternative polyadenylation (APA) in the 3' untranslated region of many synaptic transcripts between iNs from SCZ patients and healthy donors. On the cellular level, 3'APA was associated with a reduction in synaptic density of iNs. Importantly, differential APA was largely conserved between postmortem human prefrontal cortex from SCZ patients and healthy donors, and strongly enriched for transcripts related to synapse biology. 3'APA was highly correlated with SCZ polygenic risk and affected genes were significantly enriched for SCZ associated common genetic variation. Integrative functional genomic analysis identified the RNA binding protein and SCZ GWAS risk gene PTBP2 as a critical trans-acting factor mediating 3'APA of synaptic genes in SCZ subjects. Functional characterization of PTBP2 in iNs confirmed its key role in 3'APA of synaptic transcripts and regulation of synapse density. Jointly, our findings show that the aggregated effects of polygenic risk converge on 3'APA as one common molecular mechanism that underlies synaptic impairments in SCZ.
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- 2024
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174. Characterization of phospholipid-modified lung surfactant in vitro and in a neonatal ARDS model reveals anti-inflammatory potential and surfactant lipidome signatures.
- Author
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Kupsch S, Eggers LF, Spengler D, Gisch N, Goldmann T, Fehrenbach H, Stichtenoth G, Krause MF, Schwudke D, and Schromm AB
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- Animals, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Inflammasomes metabolism, Lipidomics, Lung metabolism, Phospholipids pharmacology, Surface-Active Agents, Swine, Pulmonary Surfactants metabolism, Pulmonary Surfactants pharmacology, Respiratory Distress Syndrome
- Abstract
A strong inflammatory immune response drives the lung pathology in neonatal acute respiratory distress syndrome (nARDS). Anti-inflammatory therapy is therefore a promising strategy for improved treatment of nARDS. We demonstrate a new function of the anionic phospholipids POPG, DOPG, and PIP2 as inhibitors of IL-1β release by LPS and ATP-induced inflammasome activation in human monocyte-derived and lung macrophages. Curosurf® surfactant was enriched with POPG, DOPG, PIP2 and the head-group derivative IP3, biophysically characterized and applicability was evaluated in a piglet model of nARDS. The composition of pulmonary surfactant from piglets was determined by shotgun lipidomics screens. After 72 h of nARDS, levels of POPG, DOPG, and PIP2 were enhanced in the respective treatment groups. Otherwise, we did not observe changes of individual lipid species in any of the groups. Surfactant proteins were not affected, with the exception of the IP3 treated group. Our data show that POPG, DOPG, and PIP2 are potent inhibitors of inflammasome activation; their enrichment in a surfactant preparation did not induce any negative effects on lipid profile and reduced biophysical function in vitro was mainly observed for PIP2. These results encourage to rethink the current strategies of improving surfactant preparations by inclusion of anionic lipids as potent anti-inflammatory immune regulators., (Copyright © 2022. Published by Elsevier B.V.)
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- 2022
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175. Validation of a predictive model for identifying an increased risk for recurrence in adolescents and young adults with a first provoked thromboembolism.
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Limperger V, Torge A, Kiesau B, Langer F, Kenet G, Mesters R, Juhl D, Stoll M, Shneyder M, Kowalski D, Bajorat T, Rocke A, Kuta P, Lasarow L, Spengler D, Junker R, and Nowak-Göttl U
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- Adolescent, Anticoagulants adverse effects, Humans, Male, Recurrence, Risk Factors, Young Adult, Blood Group Antigens, Thrombophilia complications, Venous Thromboembolism diagnosis, Venous Thromboembolism epidemiology, Venous Thromboembolism etiology, Venous Thrombosis
- Abstract
Background: To develop and validate a predictive model to determinate patients at increased risk to suffer from recurrence following a first provoked deep vein thrombosis (VTE)., Methods: Predictive variables, i.e. male sex [1 point], inherited thrombophilia (IT) status (none [0 points], single [1 point], combined variants [2 points]), blood group non-0, and age at first VTE onset were included into a risk assessment model, which was derived in 511 patients and then validated in 509 independent subjects., Results: VTE recurrence risk score (maximum 4 points, range 0-3) was below two for patients scored as low-risk (LRS) and ≥2 for patients at high-risk (HRS). Within a median time of 3 years after withdrawal of anticoagulation (AC) recurrence rate in LRG (derivation) was 11.8% versus 26.0% in HRS (p < 0.001). In the validation cohort within 2.2 years the recurrence rate was 9.8% in LRS versus 30.1% in HRS (p < 0.001). In multivariable analysis adjusted for age at first VTE and blood group the recurrent risk in HRS was significantly increased compared with the LRS (derivation: hazard/95% confidence interval: 3.7/1.75-7.91; validation: 4.7/2.24-9.81; combined 5.2/1.92-13.9). Model specificity (sensitivity) was 79.0% (52.0%) in the derivation cohort compared with 78.0% (43.0%) in the validation group. In conclusion, in the prediction model presented here the risk of VTE recurrence was associated with male gender and combined ITs. Based on the negative predictive value calculated the model may identify patients with a first provoked VTE not being at risk for recurrence., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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176. [Flock status - sheep flock assessment - Ressource and management related welfare indicators].
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Strobel H, Spengler D, Voigt K, and Hilke J
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- Animal Welfare, Animals, Farms, Sheep, Animal Husbandry, Sheep Diseases diagnosis, Sheep Diseases therapy
- Abstract
The welfare status of sheep flocks may be assessed via animal-, resource-, and management-related indicators. The benefits of multiple-choice questionnaires are however impaired by the diversity of sheep breeds and husbandry. From a veterinary flock health management point of view, the presented review describes the influence of environment, climate, supervision as well as additional factors under consideration of legal regulations. The improvement of welfare is a common concern of all players in the field of farm animal husbandry. Based on this, challenges as well as possibilities for improvement exist for legal and administrative institutions as well as pharmaceutical industry., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)
- Published
- 2021
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177. [Flock status - sheep flock assessment - Flock examination procedure and animal related indicators].
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Strobel H, Spengler D, and Voigt K
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- Animal Welfare, Animals, Sheep, Animal Husbandry, Sheep Diseases diagnosis
- Abstract
A protocol for the examination of sheep in an entire flock approach is suggested allowing for an acquisition of information prior to the fixation of single sheep. Data and animal based information concerning welfare are assessed and subsequent action determined. The diversity of sheep breeds and husbandry features as well as their impact on parasite management and supervision ought to be taken into account in skilled assessment of flock health and animal welfare., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)
- Published
- 2021
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178. Single-Cell Transcriptomics Supports a Role of CHD8 in Autism.
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Hoffmann A and Spengler D
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- Animals, Autistic Disorder psychology, Brain metabolism, Brain physiopathology, DNA-Binding Proteins metabolism, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Humans, Mutation, Neurogenesis, Single-Cell Analysis methods, Transcription Factors metabolism, Autistic Disorder etiology, Autistic Disorder metabolism, DNA-Binding Proteins genetics, Disease Susceptibility, Transcription Factors genetics, Transcriptome
- Abstract
Chromodomain helicase domain 8 ( CHD8 ) is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with CHD8 mutations show leading symptoms of autism, macrocephaly, and facial dysmorphisms. The molecular and cellular mechanisms underpinning the early onset and development of these symptoms are still poorly understood and prevent timely and more efficient therapies of patients. Progress in this area will require an understanding of "when, why and how cells deviate from their normal trajectories". High-throughput single-cell RNA sequencing (sc-RNAseq) directly quantifies information-bearing RNA molecules that enact each cell's biological identity. Here, we discuss recent insights from sc-RNAseq of CRISPR/Cas9-editing of Chd8/CHD8 during mouse neocorticogenesis and human cerebral organoids. Given that the deregulation of the balance between excitation and inhibition (E/I balance) in cortical and subcortical circuits is thought to represent a major etiopathogenetic mechanism in ASD, we focus on the question of whether, and to what degree, results from current sc-RNAseq studies support this hypothesis. Beyond that, we discuss the pros and cons of these approaches and further steps to be taken to harvest the full potential of these transformative techniques.
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- 2021
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179. Chromatin Remodeler CHD8 in Autism and Brain Development.
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Hoffmann A and Spengler D
- Abstract
Chromodomain Helicase DNA-binding 8 ( CHD8 ) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including 'humanized' mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.
- Published
- 2021
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180. Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders.
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Hoffmann A, Ziller M, and Spengler D
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- Causality, Genome-Wide Association Study, Humans, Human Embryonic Stem Cells pathology, Induced Pluripotent Stem Cells pathology, Mental Disorders pathology, Models, Biological
- Abstract
Genome-wide association studies (GWAS) have identified an increasing number of genetic variants that significantly associate with psychiatric disorders. Despite this wealth of information, our knowledge of which variants causally contribute to disease, how they interact, and even more so of the functions they regulate, is still poor. The availability of embryonic stem cells (ESCs) and the advent of patient-specific induced pluripotent stem cells (iPSCs) has opened new opportunities to investigate genetic risk variants in living disease-relevant cells. Here, we analyze how this progress has contributed to the analysis of causal relationships between genetic risk variants and neuronal phenotypes, especially in schizophrenia (SCZ) and bipolar disorder (BD). Studies on rare, highly penetrant risk variants have originally led the field, until more recently when the development of (epi-) genetic editing techniques spurred studies on cause-effect relationships between common low risk variants and their associated neuronal phenotypes. This reorientation not only offers new insights, but also raises issues on interpretability. Concluding, we consider potential caveats and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders.
- Published
- 2020
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181. An Unsettled Promise: The Newborn Piglet Model of Neonatal Acute Respiratory Distress Syndrome (NARDS). Physiologic Data and Systematic Review.
- Author
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Spengler D, Rintz N, and Krause MF
- Abstract
Despite great advances in mechanical ventilation and surfactant administration for the newborn infant with life-threatening respiratory failure no specific therapies are currently established to tackle major pro-inflammatory pathways. The susceptibility of the newborn infant with neonatal acute respiratory distress syndrome (NARDS) to exogenous surfactant is linked with a suppression of most of the immunologic responses by the innate immune system, however, additional corticosteroids applied in any severe pediatric lung disease with inflammatory background do not reduce morbidity or mortality and may even cause harm. Thus, the neonatal piglet model of acute lung injury serves as an excellent model to study respiratory failure and is the preferred animal model for reasons of availability, body size, similarities of porcine and human lung, robustness, and costs. In addition, similarities to the human toll-like receptor 4, the existence of intraalveolar macrophages, the sensitivity to lipopolysaccharide, and the production of nitric oxide make the piglet indispensable in anti-inflammatory research. Here we present the physiologic and immunologic data of newborn piglets from three trials involving acute lung injury secondary to repeated airway lavage (and others), mechanical ventilation, and a specific anti-inflammatory intervention via the intratracheal route using surfactant as a carrier substance. The physiologic data from many organ systems of the newborn piglet-but with preference on the lung-are presented here differentiating between baseline data from the uninjured piglet, the impact of acute lung injury on various parameters (24 h), and the follow up data after 72 h of mechanical ventilation. Data from the control group and the intervention groups are listed separately or combined. A systematic review of the newborn piglet meconium aspiration model and the repeated airway lavage model is finally presented. While many studies assessed lung injury scores, leukocyte infiltration, and protein/cytokine concentrations in bronchoalveolar fluid, a systematic approach to tackle major upstream pro-inflammatory pathways of the innate immune system is still in the fledgling stages. For the sake of newborn infants with life-threatening NARDS the newborn piglet model still is an unsettled promise offering many options to conquer neonatal physiology/immunology and to establish potent treatment modalities., (Copyright © 2019 Spengler, Rintz and Krause.)
- Published
- 2019
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182. Progress in iPSC-Based Modeling of Psychiatric Disorders.
- Author
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Hoffmann A, Ziller M, and Spengler D
- Subjects
- Animals, Hippocampus embryology, Hippocampus metabolism, Hippocampus physiopathology, Humans, Neural Stem Cells metabolism, Neurogenesis, Induced Pluripotent Stem Cells metabolism, Mental Disorders etiology, Mental Disorders metabolism, Models, Biological
- Abstract
Progress in iPSC-based cellular systems provides new insights into human brain development and early neurodevelopmental deviations in psychiatric disorders. Among these, studies on schizophrenia (SCZ) take a prominent role owing to its high heritability and multifarious evidence that it evolves from a genetically induced vulnerability in brain development. Recent iPSC studies on patients with SCZ indicate that functional impairments of neural progenitor cells (NPCs) in monolayer culture extend to brain organoids by disrupting neocorticogenesis in an in vitro model. In addition, the formation of hippocampal circuit-like structures in vitro is impaired in patients with SCZ as is the case for glia development. Intriguingly, chimeric-mice experiments show altered oligodendrocyte and astrocyte development in vivo that highlights the importance of cell-cell interactions in the pathogenesis of early-onset SCZ. Likewise, cortical imbalances in excitatory-inhibitory signaling may result from a cell-autonomous defect in cortical interneuron (cIN) development. Overall, these findings indicate that genetic risk in SCZ impacts neocorticogenesis, hippocampal circuit formation, and the development of distinct glial and neuronal subtypes. In light of this remarkable progress, we discuss current limitations and further steps necessary to harvest the full potential of iPSC-based investigations on psychiatric disorders.
- Published
- 2019
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183. Chromatin Remodeling Complex NuRD in Neurodevelopment and Neurodevelopmental Disorders.
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Hoffmann A and Spengler D
- Abstract
The nucleosome remodeling and deacetylase (NuRD) complex presents one of the major chromatin remodeling complexes in mammalian cells. Here, we discuss current evidence for NuRD's role as an important epigenetic regulator of gene expression in neural stem cell (NSC) and neural progenitor cell (NPC) fate decisions in brain development. With the formation of the cerebellar and cerebral cortex, NuRD facilitates experience-dependent cerebellar plasticity and regulates additionally cerebral subtype specification and connectivity in postmitotic neurons. Consistent with these properties, genetic variation in NuRD's subunits emerges as important risk factor in common polygenic forms of neurodevelopmental disorders (NDDs) and neurodevelopment-related psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BD). Overall, these findings highlight the critical role of NuRD in chromatin regulation in brain development and in mental health and disease.
- Published
- 2019
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184. Stress dynamically regulates co-expression networks of glucocorticoid receptor-dependent MDD and SCZ risk genes.
- Author
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Zimmermann CA, Arloth J, Santarelli S, Löschner A, Weber P, Schmidt MV, Spengler D, and Binder EB
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- Animals, Behavior, Animal, Brain metabolism, Female, Hippocampus metabolism, Humans, Male, Mice, Inbred BALB C, Paraventricular Hypothalamic Nucleus metabolism, Species Specificity, Depressive Disorder, Major genetics, Gene Regulatory Networks, Receptors, Glucocorticoid genetics, Schizophrenia genetics, Stress, Psychological genetics
- Abstract
Early-life adversity is an important risk factor for major depressive disorder (MDD) and schizophrenia (SCZ) that interacts with genetic factors to confer disease risk through mechanisms that are still insufficiently understood. One downstream effect of early-life adversity is the activation of glucocorticoid receptor (GR)-dependent gene networks that drive acute and long-term adaptive behavioral and cellular responses to stress. We have previously shown that genetic variants that moderate GR-induced gene transcription (GR-response eSNPs) are significantly enriched among risk variants from genome-wide association studies (GWASs) for MDD and SCZ. Here, we show that the 63 transcripts regulated by these disease-associated functional genetic variants form a tight glucocorticoid-responsive co-expression network (termed GCN). We hypothesized that changes in the correlation structure of this GCN may contribute to early-life adversity-associated disease risk. Therefore, we analyzed the effects of different qualities of social support and stress throughout life on GCN formation across distinct brain regions using a translational mouse model. We observed that different qualities of social experience substantially affect GCN structure in a highly brain region-specific manner. GCN changes were predominantly found in two functionally interconnected regions, the ventral hippocampus and the hypothalamus, two brain regions previously shown to be of relevance for the stress response, as well as psychiatric disorders. Overall, our results support the hypothesis that a subset of genetic variants may contribute to risk for MDD and SCZ by altering circuit-level effects of early and adult social experiences on GCN formation and structure.
- Published
- 2019
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185. The Mitochondrion as Potential Interface in Early-Life Stress Brain Programming.
- Author
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Hoffmann A and Spengler D
- Abstract
Mitochondria play a central role in cellular energy-generating processes and are master regulators of cell life. They provide the energy necessary to reinstate and sustain homeostasis in response to stress, and to launch energy intensive adaptation programs to ensure an organism's survival and future well-being. By this means, mitochondria are particularly apt to mediate brain programming by early-life stress (ELS) and to serve at the same time as subcellular substrate in the programming process. With a focus on mitochondria's integrated role in metabolism, steroidogenesis and oxidative stress, we review current findings on altered mitochondrial function in the brain, the placenta and peripheral blood cells following ELS-dependent programming in rodents and recent insights from humans exposed to early life adversity (ELA). Concluding, we propose a role of the mitochondrion as subcellular intersection point connecting ELS, brain programming and mental well-being, and a role as a potential site for therapeutic interventions in individuals exposed to severe ELS.
- Published
- 2018
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186. [Claw infections in sheep - treatment options in veterinary practice, with special emphasis on ovine footrot treatment. - An update].
- Author
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Strobel H, Hilke J, Spengler D, Axt H, Ganter M, and Voigt K
- Subjects
- Animals, Foot Rot diagnosis, Foot Rot drug therapy, Foot Rot prevention & control, Hoof and Claw physiopathology, Lameness, Animal diagnosis, Lameness, Animal drug therapy, Lameness, Animal prevention & control, Lameness, Animal therapy, Sheep, Sheep Diseases diagnosis, Sheep Diseases drug therapy, Sheep Diseases prevention & control, Anti-Bacterial Agents therapeutic use, Foot Rot therapy, Sheep Diseases therapy
- Abstract
Infectious causes of lameness in sheep remain of considerable clinical importance. Because of the availability of newly licensed drugs, important changes in therapy options, particularly for ovine footrot, have occurred. This paper provides an overview of common and rarer infectious causes of lameness in sheep, and presents a detailed review of recent advances in research regarding the aetiology, diagnosis, prevention, treatment and control of ovine foot rot. Despite the recent release of several antibiotics licensed for the treatment of footrot in sheep, the use of footbaths following the cascade of regulations remains a crucial part of many integrated treatment and control programmes. The sustainable control of foot rot requires recent advances in science to be put into practice, with tailor-made control programmes for each individual farm. The article presents various treatment options and potential routes of control and eradication., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2018
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187. Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells.
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Hoffmann A, Ziller M, and Spengler D
- Subjects
- Animals, Cell Differentiation genetics, Cell Differentiation physiology, DNA Copy Number Variations genetics, Humans, Induced Pluripotent Stem Cells cytology, MicroRNAs genetics, Induced Pluripotent Stem Cells metabolism, Schizophrenia, Childhood genetics
- Abstract
Childhood-onset schizophrenia (COS) is a rare psychiatric disorder characterized by earlier onset, more severe course, and poorer outcome relative to adult-onset schizophrenia (AOS). Even though, clinical, neuroimaging, and genetic studies support that COS is continuous to AOS. Early neurodevelopmental deviations in COS are thought to be significantly mediated through poorly understood genetic risk factors that may also predispose to long-term outcome. In this review, we discuss findings from induced pluripotent stem cells (iPSCs) that allow the generation of disease-relevant cell types from early brain development. Because iPSCs capture each donor's genotype, case/control studies can uncover molecular and cellular underpinnings of COS. Indeed, recent studies identified alterations in neural progenitor and neuronal cell function, comprising dendrites, synapses, electrical activity, glutamate signaling, and miRNA expression. Interestingly, transcriptional signatures of iPSC-derived cells from patients with COS showed concordance with postmortem brain samples from SCZ, indicating that changes in vitro may recapitulate changes from the diseased brain. Considering this progress, we discuss also current caveats from the field of iPSC-based disease modeling and how to proceed from basic studies to improved diagnosis and treatment of COS., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
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188. Supine vs. Prone Position With Turn of the Head Does Not Affect Cerebral Perfusion and Oxygenation in Stable Preterm Infants ≤32 Weeks Gestational Age.
- Author
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Spengler D, Loewe E, and Krause MF
- Abstract
Intraventricular hemorrhage (IVH) is a frequent major damage to the brain of premature babies ≤32 weeks gestational age, and its incidence (20-25%) has not significantly changed lately. Because of the intrinsic fragility of germinal matrix blood vessels, IVH occurs following disruption of subependymal mono-layer arteries and is generally attributed to ischemia-reperfusion alterations or venous congestion, which may be caused by turn of the head. Therefore, supine position with the head in a midline position is considered a standard position for preterm infants during their first days of life. We asked whether a change in body position (supine vs. prone) linked with a turn of the head by 90° in the prone position would change blood flow velocities and resistance indices in major cerebral arteries and veins of stable premature babies at two different time points (t0, day of life 2, vs. t1, day 9). Moreover, we assessed cerebral tissue oxygenation (cStO2) by near-infrared spectroscopy and determined correlations for changes in velocities and oxygenation. Twenty one premature infants [gestational age 30 (26-32) weeks] with sufficiently stable gas exchange and circulation were screened by ultrasonography and near-infrared spectroscopy. Peak systolic and end-diastolic blood flow velocities in the anterior cerebral arteries (29 ± 6 m/s vs. 28 ± 7 peak flow at t0, 36 ± 8 vs. 35 ± 7 at t1), the basilar artery, the right and the left internal carotid artery, and the great cerebral vein Galen (4.0 ± 0.8 m/s vs. 4.1 ± 1.0 maximum flow at t0, 4.4 ± 0.8 vs. 4.4 ± 1.0 at t1) did not show significant differences following change of body and head position. Also, there were no differences in cStO
2 (83 ± 7% vs. 84 ± 7 at t0, 76 ± 10 vs. 77 ± 11 at t1) and in vital signs such as heart rate and blood pressure. We conclude that change in body position with turn of the head in the prone position does not elicit significant alterations in cerebral blood flow velocities or in oxygenation of cerebral tissues. Maturational changes in arterial flow velocities and cStO2 are not correlated. For this subgroup of premature infants at low risk of IVH our data do not support the concept of exclusive preterm infant care in supine position.- Published
- 2018
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189. Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells.
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Ahmad R, Sportelli V, Ziller M, Spengler D, and Hoffmann A
- Abstract
Schizophrenia (SCZ) is a devastating mental disorder that is characterized by distortions in thinking, perception, emotion, language, sense of self, and behavior. Epidemiological evidence suggests that subtle perturbations in early neurodevelopment increase later susceptibility for disease, which typically manifests in adolescence to early adulthood. Early perturbations are thought to be significantly mediated through incompletely understood genetic risk factors. The advent of induced pluripotent stem cell (iPSC) technology allows for the in vitro analysis of disease-relevant neuronal cell types from the early stages of human brain development. Since iPSCs capture each donor's genotype, comparison between neuronal cells derived from healthy and diseased individuals can provide important insights into the molecular and cellular basis of SCZ. In this review, we discuss results from an increasing number of iPSC-based SCZ/control studies that highlight alterations in neuronal differentiation, maturation, and neurotransmission in addition to perturbed mitochondrial function and micro-RNA expression. In light of this remarkable progress, we consider also ongoing challenges from the field of iPSC-based disease modeling that call for further improvements on the generation and design of patient-specific iPSC studies to ultimately progress from basic studies on SCZ to tailored treatments.
- Published
- 2018
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190. From the Psychiatrist's Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish.
- Author
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Hoffmann A, Sportelli V, Ziller M, and Spengler D
- Subjects
- Bipolar Disorder genetics, Calcium Signaling, Cell Differentiation, Humans, Induced Pluripotent Stem Cells cytology, Membrane Potentials, Neural Stem Cells cytology, Neural Stem Cells metabolism, Neural Stem Cells physiology, Primary Cell Culture methods, Bipolar Disorder metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
Bipolar disease (BD) is one of the major public health burdens worldwide and more people are affected every year. Comprehensive genetic studies have associated thousands of single nucleotide polymorphisms (SNPs) with BD risk; yet, very little is known about their functional roles. Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype in disease-relevant tissues and cell types. Neural cells generated from BD-specific iPSCs are thought to capture associated genetic risk factors, known and unknown, and to allow the analysis of their effects on cellular and molecular phenotypes. Interestingly, an increasing number of studies on BD-derived iPSCs report distinct alterations in neural patterning, postmitotic calcium signaling, and neuronal excitability. Importantly, these alterations are partly normalized by lithium, a first line treatment in BD. In light of these exciting findings, we discuss current challenges to the field of iPSC-based disease modelling and future steps to be taken in order to fully exploit the potential of this approach for the investigation of BD and the development of new therapies., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
- Published
- 2018
- Full Text
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191. Site-specific and endothelial-mediated dysfunction of the alveolar-capillary barrier in response to lipopolysaccharides.
- Author
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Janga H, Cassidy L, Wang F, Spengler D, Oestern-Fitschen S, Krause MF, Seekamp A, Tholey A, and Fuchs S
- Subjects
- Adult, Capillaries drug effects, Caveolin 1 metabolism, Cell Line, Cell Membrane Permeability drug effects, Coculture Techniques, Electric Impedance, Endothelial Cells drug effects, Endothelial Cells metabolism, Gene Expression Regulation drug effects, Humans, Inflammation pathology, Phosphorylation drug effects, Proteomics, Pulmonary Alveoli drug effects, Pulmonary Surfactant-Associated Proteins metabolism, Tight Junction Proteins metabolism, Zonula Occludens-1 Protein metabolism, Capillaries physiopathology, Endothelial Cells pathology, Lipopolysaccharides toxicity, Pulmonary Alveoli physiopathology
- Abstract
Infectious agents such as lipopolysaccharides (LPS) challenge the functional properties of the alveolar-capillary barrier (ACB) in the lung. In this study, we analyse the site-specific effects of LPS on the ACB and reveal the effects on the individual cell types and the ACB as a functional unit. Monocultures of H441 epithelial cells and co-cultures of H441 with endothelial cells cultured on Transwells
® were treated with LPS from the apical or basolateral compartment. Barrier properties were analysed by the transepithelial electrical resistance (TEER), by transport assays, and immunostaining and assessment of tight junctional molecules at protein level. Furthermore, pro-inflammatory cytokines and immune-modulatory molecules were evaluated by ELISA and semiquantitative real-time PCR. Liquid chromatography-mass spectrometry-based proteomics (LS-MS) was used to identify proteins and effector molecules secreted by endothelial cells in response to LPS. In co-cultures treated with LPS from the basolateral compartment, we noticed a significant reduction of TEER, increased permeability and induction of pro-inflammatory cytokines. Conversely, apical treatment did not affect the barrier. No changes were noticed in H441 monoculture upon LPS treatment. However, LPS resulted in an increased expression of pro-inflammatory cytokines such as IL-6 in OEC and in turn induced the reduction of TEER and an increase in SP-A expression in H441 monoculture, and H441/OEC co-cultures after LPS treatment from basolateral compartment. LS-MS-based proteomics revealed factors associated with LPS-mediated lung injury such as ICAM-1, VCAM-1, Angiopoietin 2, complement factors and cathepsin S, emphasizing the role of epithelial-endothelial crosstalk in the ACB in ALI/ARDS., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)- Published
- 2018
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192. Novel therapeutic roles for surfactant-inositols and -phosphatidylglycerols in a neonatal piglet ARDS model: a translational study.
- Author
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Spengler D, Winoto-Morbach S, Kupsch S, Vock C, Blöchle K, Frank S, Rintz N, Diekötter M, Janga H, Weckmann M, Fuchs S, Schromm AB, Fehrenbach H, Schütze S, and Krause MF
- Subjects
- Animals, Animals, Newborn, Apoptosis, Bronchoalveolar Lavage Fluid, Cytokines genetics, Cytokines metabolism, Female, Humans, Male, NF-kappa B genetics, NF-kappa B metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Pulmonary Edema metabolism, Pulmonary Edema pathology, Pulmonary Gas Exchange, Random Allocation, Respiration, Artificial, Respiratory Distress Syndrome, Newborn metabolism, Respiratory Distress Syndrome, Newborn pathology, Swine, Translational Research, Biomedical, Vitamin B Complex pharmacology, Disease Models, Animal, Inositol pharmacology, Phosphatidylglycerols pharmacology, Pulmonary Edema drug therapy, Pulmonary Surfactants pharmacology, Respiratory Distress Syndrome, Newborn drug therapy
- Abstract
The biological and immune-protective properties of surfactant-derived phospholipids and phospholipid subfractions in the context of neonatal inflammatory lung disease are widely unknown. Using a porcine neonatal triple-hit acute respiratory distress syndrome (ARDS) model (repeated airway lavage, overventilation, and LPS instillation into airways), we assessed whether the supplementation of surfactant (S; poractant alfa) with inositol derivatives [inositol 1,2,6-trisphosphate (IP3) or phosphatidylinositol 3,5-bisphosphate (PIP2)] or phosphatidylglycerol subfractions [16:0/18:1-palmitoyloleoyl-phosphatidylglycerol (POPG) or 18:1/18:1-dioleoyl-phosphatidylglycerol (DOPG)] would result in improved clinical parameters and sought to characterize changes in key inflammatory pathways behind these improvements. Within 72 h of mechanical ventilation, the oxygenation index (S+IP3, S+PIP2, and S+POPG), the ventilation efficiency index (S+IP3 and S+POPG), the compliance (S+IP3 and S+POPG) and resistance (S+POPG) of the respiratory system, and the extravascular lung water index (S+IP3 and S+POPG) significantly improved compared with S treatment alone. The inositol derivatives (mainly S+IP3) exerted their actions by suppressing acid sphingomyelinase activity and dependent ceramide production, linked with the suppression of the inflammasome nucleotide-binding domain, leucine-rich repeat-containing protein-3 (NLRP3)-apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-caspase-1 complex, and the profibrotic response represented by the cytokines transforming growth factor-β1 and IFN-γ, matrix metalloproteinase (MMP)-1/8, and elastin. In addition, IκB kinase activity was significantly reduced. S+POPG and S+DOPG treatment inhibited polymorphonuclear leukocyte activity (MMP-8 and myeloperoxidase) and the production of interleukin-6, maintained alveolar-capillary barrier functions, and reduced alveolar epithelial cell apoptosis, all of which resulted in reduced pulmonary edema. S+DOPG also limited the profibrotic response. We conclude that highly concentrated inositol derivatives and phosphatidylglycerol subfractions in surfactant preparations mitigate key inflammatory pathways in inflammatory lung disease and that their clinical application may be of interest for future treatment of the acute exudative phase of neonatal ARDS.
- Published
- 2018
- Full Text
- View/download PDF
193. Epigenomics of Major Depressive Disorders and Schizophrenia: Early Life Decides.
- Author
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Hoffmann A, Sportelli V, Ziller M, and Spengler D
- Subjects
- Behavior, Epigenesis, Genetic, Humans, Depressive Disorder, Major genetics, Epigenomics, Life Change Events, Schizophrenia genetics
- Abstract
Brain development is guided by the interactions between the genetic blueprint and the environment. Epigenetic mechanisms, especially DNA methylation, can mediate these interactions and may also trigger long-lasting adaptations in developmental programs that increase the risk of major depressive disorders (MDD) and schizophrenia (SCZ). Early life adversity is a major risk factor for MDD/SCZ and can trigger persistent genome-wide changes in DNA methylation at genes important to early, but also to mature, brain function, including neural proliferation, differentiation, and synaptic plasticity, among others. Moreover, genetic variations controlling dynamic DNA methylation in early life are thought to influence later epigenomic changes in SCZ. This finding corroborates the high genetic load and a neurodevelopmental origin of SCZ and shows that epigenetic responses to the environment are, at least in part, genetically controlled. Interestingly, genetic variants influencing DNA methylation are also enriched in risk variants from genome-wide association studies (GWAS) on SCZ supporting a role in neurodevelopment. Overall, epigenomic responses to early life adversity appear to be controlled to different degrees by genetics in MDD/SCZ, even though the potential reversibility of epigenomic processes may offer new hope for timely therapeutic interventions in MDD/SCZ., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2017
- Full Text
- View/download PDF
194. An adverse early life environment can enhance stress resilience in adulthood.
- Author
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Santarelli S, Zimmermann C, Kalideris G, Lesuis SL, Arloth J, Uribe A, Dournes C, Balsevich G, Hartmann J, Masana M, Binder EB, Spengler D, and Schmidt MV
- Subjects
- Animals, Endophenotypes, Female, Hippocampus metabolism, Hippocampus physiopathology, Hypothalamo-Hypophyseal System physiopathology, Male, Mice, Mice, Inbred BALB C, Pituitary-Adrenal System physiopathology, Receptors, Glucocorticoid metabolism, Social Environment, Adaptation, Psychological physiology, Behavior, Animal physiology, Resilience, Psychological, Social Isolation, Stress, Psychological physiopathology
- Abstract
Chronic stress is a major risk factor for depression. Interestingly, not all individuals develop psychopathology after chronic stress exposure. In contrast to the prevailing view that stress effects are cumulative and increase stress vulnerability throughout life, the match/mismatch hypothesis of psychiatric disorders. The match/mismatch hypothesis proposes that individuals who experience moderate levels of early life psychosocial stress can acquire resilience to renewed stress exposure later in life. Here, we have tested this hypothesis by comparing the developmental effects of 2 opposite early life conditions, when followed by 2 opposite adult environments. Male Balb/c mice were exposed to either adverse early life conditions (limited nesting and bedding material) or a supportive rearing environment (early handling). At adulthood, the animals of each group were either housed with an ovariectomized female (supportive environment) or underwent chronic social defeat stress (socially adverse environment) for 3 weeks. At the end of the adult manipulations, all of the animals were returned to standard housing conditions. Then, we compared the neuroendocrine, behavioral and molecular effects of the interaction between early and adult environment. Our study shows that early life adversity does not necessarily result in increased vulnerability to stress. Specific endophenotypes, like hypothalamic-pituitary-adrenal axis activity, anxiety-related behavior and glucocorticoid receptor expression levels in the hippocampus were not significantly altered when adversity is experienced during early life and in adulthood, and are mainly affected by either early life or adult life adversity alone. Overall our data support the notion that being raised in a stressful environment prepares the offspring to better cope with a challenging adult environment and emphasize the role of early life experiences in shaping adult responsiveness to stress., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
195. The Future is The Past: Methylation QTLs in Schizophrenia.
- Author
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Hoffmann A, Ziller M, and Spengler D
- Abstract
Genome-wide association studies (GWAS) have remarkably advanced insight into the genetic basis of schizophrenia (SCZ). Still, most of the functional variance in disease risk remains unexplained. Hence, there is a growing need to map genetic variability-to-genes-to-functions for understanding the pathophysiology of SCZ and the development of better treatments. Genetic variation can regulate various cellular functions including DNA methylation, an epigenetic mark with important roles in transcription and the mediation of environmental influences. Methylation quantitative trait loci (meQTLs) are derived by mapping levels of DNA methylation in genetically different, genotyped individuals and define loci at which DNA methylation is influenced by genetic variation. Recent evidence points to an abundance of meQTLs in brain tissues whose functional contributions to development and mental diseases are still poorly understood. Interestingly, fetal meQTLs reside in regulatory domains affecting methylome reconfiguration during early brain development and are enriched in loci identified by GWAS for SCZ. Moreover, fetal meQTLs are preserved in the adult brain and could trace early epigenomic deregulation during vulnerable periods. Overall, these findings highlight the role of fetal meQTLs in the genetic risk for and in the possible neurodevelopmental origin of SCZ., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
- Full Text
- View/download PDF
196. Role of ZAC1 in transient neonatal diabetes mellitus and glucose metabolism.
- Author
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Hoffmann A and Spengler D
- Abstract
Transient neonatal diabetes mellitus 1 (TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1/HYMAI. Whereas the function of HYMAI, a non-coding mRNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest (ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of β-cell function and peripheral insulin sensitivity. Among these, upregulation of Pparγ and Tcf4 impairs insulin-secretion and β-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate β-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and β-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in β-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general.
- Published
- 2015
- Full Text
- View/download PDF
197. Molecular epigenetic switches in neurodevelopment in health and disease.
- Author
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Hoffmann A, Zimmermann CA, and Spengler D
- Abstract
Epigenetic mechanisms encode information above and beyond DNA sequence and play a critical role in brain development and the long-lived effects of environmental cues on the pre- and postnatal brain. Switch-like, rather than graded changes, illustrate par excellence how epigenetic events perpetuate altered activity states in the absence of the initial cue. They occur from early neural development to maturation and can give rise to distinct diseases upon deregulation. Many neurodevelopmental genes harbor bivalently marked chromatin domains, states of balanced inhibition, which guide dynamic "ON or OFF" decisions once the balance is tilted in response to developmental or environmental cues. Examples discussed in this review include neuronal differentiation of embryonic stem cells (ESC) into progenitors and beyond, activation of Kiss1 at puberty onset, and early experience-dependent programming of Avp, a major stress gene. At the genome-scale, genomic imprinting can be epigenetically switched on or off at select genes in a tightly controlled temporospatial manner and provides a versatile mechanism for dosage regulation of genes with important roles in stem cell quiescence or differentiation. Moreover, retrotransposition in neural progenitors provides an intriguing example of an epigenetic-like switch, which is stimulated by bivalently marked neurodevelopmental genes and possibly results in increased genomic flexibility regarding unprecedented challenge. Overall, we propose that molecular epigenetic switches illuminate the catalyzing function of epigenetic mechanisms in guiding dynamic changes in gene expression underpinning robust transitions in cellular and organismal phenotypes as well as in the mediation between dynamically changing environments and the static genetic blueprint.
- Published
- 2015
- Full Text
- View/download PDF
198. Imprinted Zac1 in neural stem cells.
- Author
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Daniel G, Schmidt-Edelkraut U, Spengler D, and Hoffmann A
- Abstract
Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.
- Published
- 2015
- Full Text
- View/download PDF
199. Role of mecp2 in experience-dependent epigenetic programming.
- Author
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Zimmermann CA, Hoffmann A, Raabe F, and Spengler D
- Abstract
Mutations in the X-linked gene MECP2, the founding member of a family of proteins recognizing and binding to methylated DNA, are the genetic cause of a devastating neurodevelopmental disorder in humans, called Rett syndrome. Available evidence suggests that MECP2 protein has a critical role in activity-dependent neuronal plasticity and transcription during brain development. Moreover, recent studies in mice show that various posttranslational modifications, notably phosphorylation, regulate Mecp2's functions in learning and memory, drug addiction, depression-like behavior, and the response to antidepressant treatment. The hypothalamic-pituitary-adrenal (HPA) axis drives the stress response and its deregulation increases the risk for a variety of mental disorders. Early-life stress (ELS) typically results in sustained HPA-axis deregulation and is a major risk factor for stress related diseases, in particular major depression. Interestingly, Mecp2 protein has been shown to contribute to ELS-dependent epigenetic programming of Crh, Avp, and Pomc, all of these genes enhance HPA-axis activity. Hereby ELS regulates Mecp2 phosphorylation, DNA binding, and transcriptional activities in a tissue-specific and temporospatial manner. Overall, these findings suggest MECP2 proteins are so far underestimated and have a more dynamic role in the mediation of the gene-environment dialog and epigenetic programming of the neuroendocrine stress system in health and disease.
- Published
- 2015
- Full Text
- View/download PDF
200. Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress.
- Author
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Bockmühl Y, Patchev AV, Madejska A, Hoffmann A, Sousa JC, Sousa N, Holsboer F, Almeida OF, and Spengler D
- Subjects
- Animals, Cells, Cultured, CpG Islands, Hypothalamus metabolism, Male, Mice, Inbred C57BL, DNA Methylation, Promoter Regions, Genetic, Receptors, Glucocorticoid metabolism, Stress, Psychological metabolism
- Abstract
Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a key role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine response to stress. We here show that ELS programs the expression of the GR gene (Nr3c1) by site-specific hypermethylation at the CpG island (CGI) shore in hypothalamic neurons that produce corticotropin-releasing hormone (Crh), thus preventing Crh upregulation under conditions of chronic stress. CpGs mapping to the Nr3c1 CGI shore region are dynamically regulated by ELS and underpin methylation-sensitive control of this region's insulation-like function via Ying Yang 1 (YY1) binding. Our results provide new insight into how a genomic element integrates experience-dependent epigenetic programming of the composite proximal Nr3c1 promoter, and assigns an insulating role to the CGI shore.
- Published
- 2015
- Full Text
- View/download PDF
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