| 1. |
- Adori, Csaba, et al.
(författare)
-
Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system : new aspects on Alzheimer's disease
- 2015
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 129:4, s. 541-563
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine beta-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 (-/-) mice and, unlike in Sstr1 (-/-) or Sstr4 (-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (< 8 months) in Sstr2 (-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.
|
|
| 2. |
- Adori, Csaba, et al.
(författare)
-
Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging
- 2021
-
Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:30
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.
|
|
| 3. |
- Bensing, Sophie, et al.
(författare)
-
Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1
- 2007
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:3, s. 949-954
-
Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies (Aabs) toward intracellular enzymes are a hallmark for APS1 and serve as diagnostic markers and predictors for disease manifestations. In this study, we aimed to identify pituitary autoantigens in patients with APS1. A pituitary cDNA expression library was screened with APS1 sera and a tudor domain containing protein 6 (TDRD6) cDNA clone was isolated. Positive immunoreactivity against in vitro translated TDRD6 fragments was shown in 42/86 (49%) APS1 patients but not in patients with other autoimmune diseases or in healthy controls. By using immunohistochemistry, sera from 3/6 APS1 patients with growth hormone (GH) deficiency showed immunostaining of a small number of guinea pig anterior pituitary cells, and 40-50% of these cells were GH-positive. No such immunostaining was seen with sera from healthy controls. The APS1 Aab-positive, GH-negative cells may represent a novel subpopulation of anterior pituitary cells. In addition, 4/6 patient sera showed staining of a fiber-plexus in the pituitary intermediate lobe recognizing enzymes of monoamine and GABA synthesis. Thus, we have identified TDRD6 as a major autoantigen in APS1 patients and shown that several sera from GH-deficient patients stain specific cell populations and nerves in the pituitary gland.
|
|
| 4. |
|
|
| 5. |
- Kessler, Jan H., et al.
(författare)
-
Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes
- 2010
-
Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 12:1, s. 45-53
-
Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C terminus of these CTL epitopes is considered to be produced by the proteasome. Here we demonstrate that the cytosolic endopeptidases nardilysin and thimet oligopeptidase (TOP) complemented proteasome activity. Nardilysin and TOP were required, either together or alone, for the generation of a tumor-specific CTL epitope from PRAME, an immunodominant CTL epitope from Epstein-Barr virus protein EBNA3C, and a clinically important epitope from the melanoma protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing, and nardilysin contributed to both the C-terminal and N-terminal generation of CTL epitopes. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.
|
|
| 6. |
- Mulder, Skander, et al.
(författare)
-
A metabolomics-based molecular pathway analysis of how the sodium-glucose co-transporter-2 inhibitor dapagliflozin may slow kidney function decline in patients with diabetes
- 2020
-
Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326. ; 22:7, s. 1157-1166
-
Tidskriftsartikel (refereegranskat)abstract
- Aim To investigate which metabolic pathways are targeted by the sodium-glucose co-transporter-2 inhibitor dapagliflozin to explore the molecular processes involved in its renal protective effects. Methods An unbiased mass spectrometry plasma metabolomics assay was performed on baseline and follow-up (week 12) samples from the EFFECT II trial in patients with type 2 diabetes with non-alcoholic fatty liver disease receiving dapagliflozin 10 mg/day (n = 19) or placebo (n = 6). Transcriptomic signatures from tubular compartments were identified from kidney biopsies collected from patients with diabetic kidney disease (DKD) (n = 17) and healthy controls (n = 30) from the European Renal cDNA Biobank. Serum metabolites that significantly changed after 12 weeks of dapagliflozin were mapped to a metabolite-protein interaction network. These proteins were then linked with intra-renal transcripts that were associated with DKD or estimated glomerular filtration rate (eGFR). The impacted metabolites and their protein-coding transcripts were analysed for enriched pathways. Results Of all measured (n = 812) metabolites, 108 changed (P < 0.05) during dapagliflozin treatment and 74 could be linked to 367 unique proteins/genes. Intra-renal mRNA expression analysis of the genes encoding the metabolite-associated proteins using kidney biopsies resulted in 105 genes that were significantly associated with eGFR in patients with DKD, and 135 genes that were differentially expressed between patients with DKD and controls. The combination of metabolites and transcripts identified four enriched pathways that were affected by dapagliflozin and associated with eGFR: glycine degradation (mitochondrial function), TCA cycle II (energy metabolism), L-carnitine biosynthesis (energy metabolism) and superpathway of citrulline metabolism (nitric oxide synthase and endothelial function). Conclusion The observed molecular pathways targeted by dapagliflozin and associated with DKD suggest that modifying molecular processes related to energy metabolism, mitochondrial function and endothelial function may contribute to its renal protective effect.
|
|
| 7. |
- Alling, Vanja, et al.
(författare)
-
The role of biochar in retaining nutrients in amended tropical soils
- 2014
-
Ingår i: Journal of Plant Nutrition And Soil Science/Zeitschrift für Pflanzenernahrung und Bodenkunde. - : Wiley. - 1436-8730 .- 1522-2624. ; 177:5, s. 671-680
-
Tidskriftsartikel (refereegranskat)abstract
- This study investigated the effect of biochar amendments on the retention and availability of plant nutrients and Al in seven acidic tropical soils from Zambia and Indonesia. The experiments carried out investigated whether the adsorption capacity of NH4+ in the soils increased upon the addition of biochar and which effect biochar had on available concentrations of NO3-, K+, Mn2+, Mg2+, PO43-, and Al3+. These nutrients were selected as they represent those important to plant growth and soil quality. No significant increases or decreases in aqueous NH4+-N concentration with additions of biochar were detected. The Gaines-Thomas model was used in order to calculate selectivity coefficients for NH4+ exchange (K-gt values). Following the addition of biochar to soil, K-gt values decreased showing a reduction in the selective binding of NH4+ in the biochar amended soil compared to the control. The concentration of NO3- increased following the addition of biochar to the soils. The addition of 5 and 10% biochar to the Indonesian soil did not significantly alter (t-test confidence level 0.05) the sorption of PO43- to the soil-biochar mixtures as compared to the soil alone. However, the addition of biochar to the soil from Zambia increased the sorption of PO43- compared to the soil alone. The concentrations of K+ and Mg2+ were significantly increased for almost all soils (t-test at the 0.05 confidence level) following the addition of biochar. Addition of biochar to all but two soils significantly decreased (t-test confidence level 0.05) Mn2+ concentrations. The concentration of Al3+ in the soils decreased exponentially significantly (t-test confidence level 0.05) following the amendment of biochar in accordance with the increase in pH observed when biochar was added to the soil. These results show that biochar has the ability to release essential plant growth nutrients as well as alleviate Al toxicity in these soils.
|
|
| 8. |
- Ayoglu, Burcu, et al.
(författare)
-
Anoctamin 2 identified as an autoimmune target in multiple sclerosis
- 2016
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences of the USA. - 0027-8424 .- 1091-6490. ; 113:8, s. 2188-2193
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
|
|
| 9. |
- Barde, Swapnali, et al.
(författare)
-
Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons
- 2024
-
Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 78, s. 54-63
-
Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.
|
|
| 10. |
- Bazov, Igor, 1973-, et al.
(författare)
-
Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain
- 2018
-
Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 28:9, s. 3129-3142
-
Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.
|
|
| 11. |
- Burkhard, Benjamin, et al.
(författare)
-
Mapping and assessing ecosystem services in the EU - Lessons learned from the ESMERALDA approach of integration
- 2018
-
Ingår i: One Ecosystem. - : Pensoft Publishers. - 2367-8194. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- The European Union (EU) Horizon 2020 Coordination and Support Action ESMERALDA aimed at developing guidance and a flexible methodology for Mapping and Assessment of Ecosystems and their Services (MAES) to support the EU member states in the implementation of the EU Biodiversity Strategy’s Target 2 Action 5. ESMERALDA’s key tasks included network creation, stakeholder engagement, enhancing ecosystem services mapping and assessment methods across various spatial scales and value domains, work in case studies and support of EU member states in MAES implementation. Thus ESMERALDA aimed at integrating various project outcomes around four major strands: i) Networking, ii) Policy, iii) Research and iv) Application. The objective was to provide guidance for integrated ecosystem service mapping and assessment that can be used for sustainable decision-making in policy, business, society, practice and science at EU, national and regional levels. This article presents the overall ESMERALDA approach of integrating the above-mentioned project components and outcomes and provides an overview of how the enhanced methods were applied and how they can be used to support MAES implementation in the EU member states. Experiences with implementing such a large pan-European Coordination and Support Action in the context of EU policy are discussed and recommendations for future actions are given.
|
|
| 12. |
|
|
| 13. |
- Dijksterhuis, Jacomijn P., et al.
(författare)
-
High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes
- 2015
-
Ingår i: Experimental Cell Research. - : Elsevier. - 0014-4827 .- 1090-2422. ; 339:2, s. 280-288
-
Tidskriftsartikel (refereegranskat)abstract
- Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma.
|
|
| 14. |
- Dirks-Mulder, Anita, et al.
(författare)
-
Exploring the evolutionary origin of floral organs of Erycina pusilla, an emerging orchid model system
- 2017
-
Ingår i: BMC Evolutionary Biology. - : BIOMED CENTRAL LTD. - 1471-2148. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Thousands of flowering plant species attract pollinators without offering rewards, but the evolution of this deceit is poorly understood. Rewardless flowers of the orchid Erycina pusilla have an enlarged median sepal and incised median petal ('lip') to attract oil-collecting bees. These bees also forage on similar looking but rewarding Malpighiaceae flowers that have five unequally sized petals and gland-carrying sepals. The lip of E. pusilla has a 'callus' that, together with winged 'stelidia', mimics these glands. Different hypotheses exist about the evolutionary origin of the median sepal, callus and stelidia of orchid flowers. Results: The evolutionary origin of these organs was investigated using a combination of morphological, molecular and phylogenetic techniques to a developmental series of floral buds of E. pusilla. The vascular bundle of the median sepal indicates it is a first whorl organ but its convex epidermal cells reflect convergence of petaloid features. Expression of AGL6 EpMADS4 and APETALA3 EpMADS14 is low in the median sepal, possibly correlating with its petaloid appearance. A vascular bundle indicating second whorl derivation leads to the lip. AGL6 EpMADS5 and APETALA3 EpMADS13 are most highly expressed in lip and callus, consistent with current models for lip identity. Six vascular bundles, indicating a stamen-derived origin, lead to the callus, stelidia and stamen. AGAMOUS is not expressed in the callus, consistent with its sterilization. Out of three copies of AGAMOUS and four copies of SEPALLATA, EpMADS22 and EpMADS6 are most highly expressed in the stamen. Another copy of AGAMOUS, EpMADS20, and the single copy of SEEDSTICK, EpMADS23, are most highly expressed in the stelidia, suggesting EpMADS22 may be required for fertile stamens. Conclusions: The median sepal, callus and stelidia of E. pusilla appear to be derived from a sepal, a stamen that gained petal identity, and stamens, respectively. Duplications, diversifying selection and changes in spatial expression of different MADS-box genes shaped these organs, enabling the rewardless flowers of E. pusilla to mimic an unrelated rewarding flower for pollinator attraction. These genetic changes are not incorporated in current models and urge for a rethinking of the evolution of deceptive flowers.
|
|
| 15. |
- Escudier, Bernard, et al.
(författare)
-
Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma.
- 2009
-
Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 27:25, s. 4068-4075
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen. PATIENTS AND METHODS: Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures. RESULTS: One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM. CONCLUSION: Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.
|
|
| 16. |
- Fetissov, Sergueï O, et al.
(författare)
-
Autoantibodies in autoimmune polyglandular syndrome type I patients react with major brain neurotransmitter systems.
- 2009
-
Ingår i: The Journal of comparative neurology. - : Wiley. - 1096-9861 .- 0021-9967. ; 513:1, s. 1-20
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with autoimmune polyglandular syndrome type I (APS1) often display high titers of autoantibodies (autoAbs) directed against aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and glutamic acid decarboxylase (GAD). Neurological symptoms, including stiff-man syndrome and cerebellar ataxia, can occur in subjects with high levels of GAD autoAbs, particularly when patient sera can immunohistochemically stain gamma-aminobutyric acid (GABA) neurons. However, it was not known if APS1 sera can also stain major monoamine systems in the brain. Therefore, in this work we applied sera from 17 APS1 patients known to contain autoAbs against AADC, TH, TPH, and/or GAD to rat brain sections and processed the sections according to the sensitive immunohistochemical tyramide signal amplification method. We found that autoAbs in sera from 11 patients were able to stain AADC-containing dopaminergic, serotonergic, and noradrenergic as well as AADC only (D-group) neurons and fibers in the rat brain, in several cases with a remarkably high quality and sensitivity (dilution up to 1:1,000,000); and, since they are human antibodies, they offer a good opportunity for performing multiple-labeling experiments using antibodies from other species. Six APS1 sera also stained GABAergic neuronal circuitries. Similar results were obtained in the mouse and primate brain. Our data demonstrate that many APS1 sera can immunostain the major monoamine and GABA systems in the brain. Only in a few cases, however, there was evidence that these autoAbs can be associated with neurological manifestations in APS1 patients, as, e.g., shown in previous studies in stiff-man syndrome.
|
|
| 17. |
- Gultekin, Okan, et al.
(författare)
-
FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation
- 2021
-
Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 5:1
-
Tidskriftsartikel (refereegranskat)abstract
- Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments.
|
|
| 18. |
- Han, L., et al.
(författare)
-
Cell transcriptomic atlas of the non-human primate Macaca fascicularis
- 2022
-
Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 604:7907, s. 723-731
-
Tidskriftsartikel (refereegranskat)abstract
- Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell–cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.
|
|
| 19. |
- Hines, Jes, et al.
(författare)
-
Towards an integration of biodiversity-ecosystem functioning and food web theory to evaluate relationships between multiple ecosystem services
- 2015
-
Ingår i: Advances in Ecological Research. - : Elsevier. - 0065-2504. ; 53, s. 161-199
-
Tidskriftsartikel (refereegranskat)abstract
- Ecosystem responses to changes in species diversity are often studied individually. However, changes in species diversity can simultaneously influence multiple interdependent ecosystem functions. Therefore, an important challenge is to determine when and how changes in species diversity that influence one function will also drive changes in other functions. By providing the underlying structure of species interactions, ecological networks can quantify connections between biodiversity and multiple ecosystem functions. Here, we review parallels in the conceptual development of biodiversity- ecosystem functioning (BEF) and food web theory (FWT) research. Subsequently, we evaluate three common principles that unite these two research areas by explaining the patterns, concentrations, and direction of the flux of nutrients and energy through the species in diverse interaction webs. We give examples of combined BEF-FWT approaches that can be used to identify vulnerable species and habitats and to evaluate links that drive trade-offs between multiple ecosystems functions. These combined approaches reflect promising trends towards better management of biodiversity in landscapes that provide essential ecosystem services supporting human well-being.
|
|
| 20. |
- Hoeve, Machteld, et al.
(författare)
-
The association between childhood maltreatment, mental health problems, and aggression in justice-involved boys
- 2015
-
Ingår i: Aggressive Behavior. - Hoboken, USA : Wiley-Blackwell. - 0096-140X .- 1098-2337. ; 41:5, s. 488-501
-
Tidskriftsartikel (refereegranskat)abstract
- The link between childhood maltreatment and adolescent aggression is well documented; yet, studies examining potential mechanisms that explain this association are limited. In the present study, we tested the association between childhood maltreatment and adolescent aggression in boys in juvenile justice facilities (N = 767) and examined the contribution of mental health problems to this relationship. Data on childhood maltreatment, mental health problems, and aggression were collected by means of self-report measures and structural equation models were used to test mediation models. We found that mental health problems mediated the link between maltreatment and aggression. Results demonstrated different pathways depending on the type of aggression examined. The association between childhood maltreatment and reactive aggression was fully mediated by a variety of mental health problems and for proactive aggression the association was partially mediated by mental health problems. We also found that reactive and proactive aggression partially mediated the association between maltreatment and mental health problems. These findings suggest that a transactional model may best explain the negative effects of childhood trauma on mental health problems and (in particular reactive) aggression. In addition, our findings add to the existing evidence that reactive and proactive aggression have different etiological pathways.
|
|
| 21. |
|
|
| 22. |
- Huang, Jinrong, et al.
(författare)
-
A porcine brain-wide RNA editing landscape
- 2021
-
Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 4:1
-
Tidskriftsartikel (refereegranskat)abstract
- Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is an essential post-transcriptional modification. Although hundreds of thousands of RNA editing sites have been reported in mammals, brain-wide analysis of the RNA editing in the mammalian brain remains rare. Here, a genome-wide RNA-editing investigation is performed in 119 samples, representing 30 anatomically defined subregions in the pig brain. We identify a total of 682,037 A-to-I RNA editing sites of which 97% are not identified before. Within the pig brain, cerebellum and olfactory bulb are regions with most edited transcripts. The editing level of sites residing in protein-coding regions are similar across brain regions, whereas region-distinct editing is observed in repetitive sequences. Highly edited conserved recoding events in pig and human brain are found in neurotransmitter receptors, demonstrating the evolutionary importance of RNA editing in neurotransmission functions. Although potential data biases caused by age, sex or health status are not considered, this study provides a rich resource to better understand the evolutionary importance of post-transcriptional RNA editing. Huang et al performed a genome-wide RNA editing investigation in the porcine brain in which they found over 680,000 A-to-I RNA editing sites. They identified conserved recoding events between pig and human brains thus providing an extensive resource to aid our understanding of the evolutionary importance of post-transcriptional RNA editing.
|
|
| 23. |
- Iles, Mark M., et al.
(författare)
-
A variant in FTO shows association with melanoma risk not due to BMI
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:4, s. 428-432
-
Tidskriftsartikel (refereegranskat)abstract
- We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
|
|
| 24. |
- Just, David, et al.
(författare)
-
Exploring autoantibody signatures in brain tissue from patients with severe mental illness
- 2020
-
Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- In recent years, studies have shown higher prevalence of autoantibodies in patients with schizophrenia compared to healthy individuals. This study applies an untargeted and a targeted affinity proteomics approach to explore and characterize the autoantibody repertoire in brain tissues from 73 subjects diagnosed with schizophrenia and 52 control subjects with no psychiatric or neurological disorders. Selected brain tissue lysates were first explored for IgG reactivity on planar microarrays composed of 11,520 protein fragments representing 10,820 unique proteins. Based on these results of ours and other previous studies of autoantibodies related to psychosis, we selected 226 fragments with an average length of 80 amino acids, representing 127 unique proteins. Tissue-based analysis of IgG reactivities using antigen suspension bead arrays was performed in a multiplex and parallel fashion for all 125 subjects. Among the detected autoantigens, higher IgG reactivity in subjects with schizophrenia, as compared to psychiatrically healthy subjects, was found against the glutamate ionotropic receptor NMDA type subunit 2D (anti-GluN2D). In a separate cohort with serum samples from 395 young adults with a wider spectrum of psychiatric disorders, higher levels of serum autoantibodies targeting GluN2D were found when compared to 102 control individuals. By further validating GluN2D and additional potential autoantigens, we will seek insights into how these are associated with severe mental illnesses.
|
|
| 25. |
|
|
