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- Abudurexiti, A, et al.
(author)
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Taxonomy of the order Bunyavirales: update 2019
- 2019
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In: Archives of virology. - : Springer Science and Business Media LLC. - 1432-8798 .- 0304-8608. ; 164:7, s. 1949-1965
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Journal article (peer-reviewed)
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| 7. |
- Akbarian, S, et al.
(author)
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The PsychENCODE project
- 2015
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In: Nature neuroscience. - : Springer Science and Business Media LLC. - 1546-1726 .- 1097-6256. ; 18:12, s. 1707-1712
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Journal article (peer-reviewed)
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| 9. |
- Yuen, RKC, et al.
(author)
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Genome-wide characteristics of de novo mutations in autism
- 2016
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In: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 1, s. 160271-1602710
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Journal article (peer-reviewed)abstract
- De novo mutations (DNMs) are important in autism spectrum disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole-genome sequencing (WGS) of 200 ASD parent–child trios and characterised germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (P=4.2×10−10). However, when clustered DNMs (those within 20 kb) were found in ASD, not only did they mostly originate from the mother (P=7.7×10−13), but they could also be found adjacent to de novo copy number variations where the mutation rate was significantly elevated (P=2.4×10−24). By comparing with DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (P=8.0×10−9; odds ratio=1.84), of which 15.6% (P=4.3×10−3) and 22.5% (P=7.0×10−5) were non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, regulatory sequences involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD-risk and epigenetic genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the aetiology of ASD.
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- Su, W, et al.
(author)
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Liver X receptor β increases aquaporin 2 protein level via a posttranscriptional mechanism in renal collecting ducts
- 2017
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In: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 312:4, s. F619-F628
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Journal article (peer-reviewed)abstract
- Liver X receptors (LXRs) including LXRα and LXRβ are nuclear receptor transcription factors and play an important role in lipid and glucose metabolism. It has been previously reported that mice lacking LXRβ but not LXRα develop a severe urine concentrating defect, likely via a central mechanism. Here we provide evidence that LXRβ regulates water homeostasis through increasing aquaporin 2 (AQP2) protein levels in renal collecting ducts. LXRβ−/− mice exhibited a reduced response to desmopressin (dDAVP) stimulation, suggesting that the diabetes insipidus phenotype is of both central and nephrogenic origin. AQP2 protein abundance in the renal inner medulla was significantly reduced in LXRβ−/− mice but with little change in AQP2 mRNA levels. In vitro studies showed that AQP2 protein levels were elevated upon LXR agonist treatment in both primary cultured mouse inner medullary duct cells (mIMCD) and the mIMCD3 cell line with stably expressed AQP2. In addition, LXR agonists including TO901317 and GW3965 failed to induce AQP2 gene transcription but diminished its protein ubiquitination in primary cultured mIMCD cells, thereby inhibiting its degradation. Moreover, LXR activation-induced AQP2 protein expression was abolished by the protease inhibitor MG132 and the ubiquitination-deficient AQP2 (K270R). Taken together, the present study demonstrates that activation of LXRβ increases AQP2 protein levels in the renal collecting ducts via a posttranscriptional mechanism. As such, LXRβ represents a key regulator of body water homeostasis.
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- Chittezhath, M, et al.
(author)
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Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes
- 2019
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 317:6, s. E1108-E1120
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Journal article (peer-reviewed)abstract
- β-Cells respond to peripheral insulin resistance by first increasing circulating insulin during diabetes. Islet remodeling supports this compensation, but its drivers remain poorly understood. Infiltrating macrophages have been implicated in late-stage type 2 diabetes, but relatively little is known on islet resident macrophages, especially during compensatory hyperinsulinemia. We hypothesized that islet resident macrophages would contribute to islet vascular remodeling and hyperinsulinemia during diabetes, the failure of which results in a rapid progression to frank diabetes. We used chemical (clodronate), genetics (CD169-diphtheria toxin receptor mice), or antibody-mediated (colony-stimulating factor 1 receptor α) macrophage ablation methods in diabetic (db/db) and diet-induced models of compensatory hyperinsulinemia to investigate the role of macrophages in islet remodeling. We transplanted islets devoid of macrophages into naïve diabetic mice and assessed the impact on islet vascularization. With the use of the above methods, we showed that macrophage depletion significantly and consistently compromised islet remodeling in terms of size, vascular density, and insulin secretion capacity. Depletion of islet macrophages reduced VEGF-A secretion in both human and mouse islets ex vivo, and this functionally translated to delayed revascularization upon transplantation in vivo. We revealed that islet resident macrophages were associated with islet remodeling and increased insulin secretion during diabetes. This suggests utility in harnessing islet macrophages during this phase to promote islet vascularization, remodeling, and insulin secretion.
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| 17. |
- Hong, S, et al.
(author)
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Stereoselective Synthesis of Maresin-like Lipid Mediators
- 2019
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In: Synlett : accounts and rapid communications in synthetic organic chemistry. - : Georg Thieme Verlag KG. - 0936-5214. ; 30:3, s. 343-347
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Journal article (peer-reviewed)abstract
- 14S,22-Dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (maresin-L1) and 14R,22-dihydroxy-docosa-4Z,7Z,10Z, 12E,16Z,19Z-hexaenoic acid (maresin-L2) were chemically synthesized. They were identical to activated macrophage-produced counterparts and their total synthesis was highly stereoselective, as revealed by chiral LC-UV-MS/MS analysis. The synthesis involved the following steps: (1) kinetic resolution of a racemic allylic alcohol by the asymmetric epoxidation; (2) transformation of the epoxy alcohol to γ-hydroxyenal derivative; and (3) the Wittig reaction to furnish the Z-olefin.
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| 21. |
- Sng, MK, et al.
(author)
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Selective deletion of PPARβ/δ in fibroblasts causes dermal fibrosis by attenuated LRG1 expression
- 2018
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In: Cell discovery. - : Springer Science and Business Media LLC. - 2056-5968. ; 4, s. 15-
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Journal article (peer-reviewed)abstract
- Connective tissue diseases of the skin are characterized by excessive collagen deposition in the skin and internal organs. Fibroblasts play a pivotal role in the clinical presentation of these conditions. Nuclear receptor peroxisome-proliferator activated receptors (PPARs) are therapeutic targets for dermal fibrosis, but the contribution of the different PPAR subtypes are poorly understood. Particularly, the role of fibroblast PPARβ/δ in dermal fibrosis has not been elucidated. Thus, we generated a mouse strain with selective deletion of PPARβ/δ in the fibroblast (FSPCre-Pparb/d−/−) and interrogated its epidermal and dermal transcriptome profiles. We uncovered a downregulated gene, leucine-rich alpha-2-glycoprotein-1 (Lrg1), of previously unknown function in skin development and architecture. Our findings suggest that the regulation of Lrg1 by PPARβ/δ in fibroblasts is an important signaling conduit integrating PPARβ/δ and TGFβ1-signaling networks in skin health and disease. Thus, the FSPCre-Pparb/d−/− mouse model could serve as a novel tool in the current gunnery of animal models to better understand dermal fibrosis.
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| 24. |
- Wang, HH, et al.
(author)
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Prenatal High Estradiol Exposure Induces Sex-Specific and Dietarily Reversible Insulin Resistance Through Decreased Hypothalamic INSR
- 2018
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In: Endocrinology. - : The Endocrine Society. - 1945-7170. ; 159:1, s. 465-476
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Journal article (peer-reviewed)abstract
- An adverse intrauterine environment may induce adult disease in offspring, but the mechanisms are not well understood. It is reported that fresh embryo transfer (ET) in assisted reproductive technology leads to high maternal estradiol (E2), and prenatal high E2 exposure increases the risk of organ disorders in later life. We found that male newborns and children of fresh ET showed elevated fasting insulin and homeostasis model of assessment for insulin resistance index (HOMA-IR) scores. Male mice with high prenatal estradiol exposure (HE) grew heavier than control mice and developed insulin resistance; they also showed increased food intake, with increased orexigenic hypothalamic neuropeptide Y (NPY) expression. The hypothalamic insulin receptor (INSR) was decreased in male HE mice, associated with elevated promoter methylation. Chronic food restriction (FR) in HE mice reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated Insr promoter methylation. Our findings suggest that prenatal exposure to high E2 may induce sex-specific metabolic disorders in later life through epigenetic programming of hypothalamic Insr promoter, and dietary intervention may reverse insulin resistance by remodeling its methylation pattern.
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