| 1. |
- Chang, Hong, et al.
(författare)
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Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1.
- 2017
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Ingår i: Molecular neurobiology. - : Springer Science and Business Media LLC. - 1559-1182 .- 0893-7648. ; 54:7
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta = 5.72 × 10(-4)), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10(-16)). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a "proxy phenotype" of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2 Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis.
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| 2. |
- Hecker, Andreas, et al.
(författare)
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Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1 beta Release
- 2015
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 195:5, s. 2325-2334
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Tidskriftsartikel (refereegranskat)abstract
- IL-1 beta is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1 beta plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1 beta release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro-IL-1 beta synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro-IL-1 beta by caspase-1, and release of mature IL-1 beta. Mechanisms controlling IL-1 beta release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1 beta release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits alpha 7, alpha 9, and/or alpha 10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1 beta and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.
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| 3. |
- Sartelli, Massimo, et al.
(författare)
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Ten golden rules for optimal antibiotic use in hospital settings: the WARNING call to action
- 2023
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Ingår i: WORLD JOURNAL OF EMERGENCY SURGERY. - 1749-7922. ; 18:1
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Forskningsöversikt (refereegranskat)abstract
- Antibiotics are recognized widely for their benefits when used appropriately. However, they are often used inappropriately despite the importance of responsible use within good clinical practice. Effective antibiotic treatment is an essential component of universal healthcare, and it is a global responsibility to ensure appropriate use. Currently, pharmaceutical companies have little incentive to develop new antibiotics due to scientific, regulatory, and financial barriers, further emphasizing the importance of appropriate antibiotic use. To address this issue, the Global Alliance for Infections in Surgery established an international multidisciplinary task force of 295 experts from 115 countries with different backgrounds. The task force developed a position statement called WARNING (Worldwide Antimicrobial Resistance National/International Network Group) aimed at raising awareness of antimicrobial resistance and improving antibiotic prescribing practices worldwide. The statement outlined is 10 axioms, or "golden rules," for the appropriate use of antibiotics that all healthcare workers should consistently adhere in clinical practice.
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| 4. |
- Shanks, Carly M., et al.
(författare)
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Role of BASIC PENTACYSTEINE transcription factors in a subset of cytokinin signaling responses
- 2018
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Ingår i: The Plant Journal. - : John Wiley & Sons. - 0960-7412 .- 1365-313X. ; 95:3, s. 458-473
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Tidskriftsartikel (refereegranskat)abstract
- Cytokinin plays diverse roles in plant growth and development, generally acting by modulating gene transcription in target tissues. The type-B Arabidopsis response regulators (ARR) transcription factors have emerged as primary targets of cytokinin signaling and are required for essentially all cytokinin-mediated changes in gene expression. The diversity of cytokinin function is likely imparted by the activity of various transcription factors working with the type-B ARRs to alter specific sets of target genes. One potential set of co-regulators modulating the cytokinin response are the BARLEY B-RECOMBINANT/BASIC PENTACYSTEINE (BBR/BPC) family of plant-specific transcription factors. Here, we show that disruption of multiple BPCs results in reduced sensitivity to cytokinin. Further, the BPCs are necessary for the induction of a subset of genes in response to cytokinin. We identified direct invivo targets of BPC6 using ChIP-Seq and found an enrichment of promoters of genes differentially expressed in response to cytokinin. Further, a significant number of BPC6 regulated genes are also direct targets of the type-B ARRs. Potential cis-binding elements for a number of other transcription factors linked to cytokinin action are enriched in the BPC binding fragments, including those for the cytokinin response factors (CRFs). In addition, several BPCs interact with a subset of type-A ARRs. Consistent with these results, a significant number of genes whose expression is altered in bpc mutant roots are also mis-expressed in crf1,3,5,6 and type-A arr3,4,5,6,7,8,9,15 mutant roots. These results suggest that the BPCs are part of a complex network of transcription factors that are involved in the response to cytokinin.
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