| 1. |
- Ha, Van Thai, et al.
(författare)
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Synergy between 15-lipoxygenase and secreted PLA(2) promotes inflammation by formation of TLR4 agonists from extracellular vesicles
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:41, s. 25679-25689
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Tidskriftsartikel (refereegranskat)abstract
- Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2 activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2 promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2 enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.
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| 2. |
- Jackson, Nicholas J., et al.
(författare)
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Impact of adolescent marijuana use on intelligence : Results from two longitudinal twin studies
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:5, s. E500-E508
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Tidskriftsartikel (refereegranskat)abstract
- Marijuana is one of the most commonly used drugs in the United States, and use during adolescence-when the brain is still developing-has been proposed as a cause of poorer neurocognitive outcome. Nonetheless, research on this topic is scarce and often shows conflicting results, with some studies showing detrimental effects of marijuana use on cognitive functioning and others showing no significant long-term effects. The purpose of the present study was to examine the associations of marijuana use with changes in intellectual performance in two longitudinal studies of adolescent twins (n = 789 and n = 2,277). We used a quasiexperimental approach to adjust for participants' family background characteristics and genetic propensities, helping us to assess the causal nature of any potential associations. Standardized measures of intelligence were administered at ages 9-12 y, before marijuana involvement, and again at ages 17-20 y. Marijuana use was self-reported at the time of each cognitive assessment as well as during the intervening period. Marijuana users had lower test scores relative to nonusers and showed a significant decline in crystallized intelligence between preadolescence and late adolescence. However, there was no evidence of a dose-response relationship between frequency of use and intelligence quotient (IQ) change. Furthermore, marijuana-using twins failed to show significantly greater IQ decline relative to their abstinent siblings. Evidence from these two samples suggests that observed declines in measured IQ may not be a direct result of marijuana exposure but rather attributable to familial factors that underlie both marijuana initiation and low intellectual attainment.
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| 3. |
- Lopez-Rivas, Abelardo, et al.
(författare)
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Ca2+-mobilizing actions of platelet-derived growth factor differ from those of bombesin and vasopressin in Swiss 3T3 mouse cells
- 1987
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 84:16, s. 5768-5772
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Tidskriftsartikel (refereegranskat)abstract
- Addition of the mitogenic peptides bombesin and vasopressin to quiescent Swiss 3T3 mouse cells increased the cytosolic Ca2+ concentration without any measurable delay. In contrast, there was a significant lag period (16 +/- 1.2 s) before platelet-derived growth factor (PDGF) increased cytosolic Ca2+ concentration. This lag was not diminished at high concentrations of either porcine or human PDGF. Similar results were obtained in 3T3 cells loaded with quin-2 or fura-2. The differences in the effects of bombesin, vasopressin, and PDGF on Ca2+ movements were also substantiated by measurements of 45Ca2+ efflux and of cellular 45Ca2+ content. Activation of protein kinase C by phorbol esters inhibited Ca2+ mobilization induced by either bombesin or vasopressin. In contrast, phorbol esters had no effect on PDGF-induced cytosolic Ca2+ concentration increase or acceleration of 45Ca2+ efflux. Finally, bombesin and vasopressin caused a rapid increase in the production of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate, whereas PDGF, even at a saturating concentration, exerted only a small effect. These results indicate that the signal transduction pathways activated by PDGF that lead to Ca2+ mobilization can be distinguished from those utilized by bombesin and vasopressin.
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| 4. |
- Matusovsky, Oleg S., et al.
(författare)
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High-speed AFM reveals subsecond dynamics of cardiac thin filaments upon Ca2+ activation and heavy meromyosin binding
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:33, s. 16384-16393
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Tidskriftsartikel (refereegranskat)abstract
- High-speed atomic force microscopy (HS-AFM) can be used to study dynamic processes with real-time imaging of molecules within 1- to 5-nm spatial resolution. In the current study, we evaluated the 3-state model of activation of cardiac thin filaments (cTFs) isolated as a complex and deposited on a mica-supported lipid bilayer. We studied this complex for dynamic conformational changes 1) at low and high [Ca2+] (pCa 9.0 and 4.5), and 2) upon myosin binding to the cTF in the nucleotide-free state or in the presence of ATP. HS-AFM was used to directly visualize the tropo-myosin-troponin complex and Ca2+-induced tropomyosin movements accompanied by structural transitions of actin monomers within cTFs. Our data show that cTFs at relaxing or activating conditions are not ultimately in a blocked or activated state, respectively, but rather the combination of states with a prevalence that is dependent on the [Ca2+] and the presence of weakly or strongly bound myosin. The weakly and strongly bound myosin induce similar changes in the structure of cTFs as confirmed by the local dynamical displacement of individual tropomyosin strands in the center of a regulatory unit of cTF at the relaxed and activation conditions. The displacement of tropomyosin at the relaxed conditions had never been visualized directly and explains the ability of myosin binding to TF at the relaxed conditions. Based on the ratios of nonactivated and activated segments within cTFs, we proposed a mechanism of tropomyosin switching from different states that includes both weakly and strongly bound myosin.
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| 5. |
- Oksman-Caldentey, Kirsi-Marja, et al.
(författare)
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Connecting genes to metabolites by a systems biology approach
- 2004
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 101:27, s. 9949-9950
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Reichenberg, Abraham, et al.
(författare)
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Discontinuity in the genetic and environmental causes of the intellectual disability spectrum
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington DC, USA : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:4, s. 1098-1103
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Tidskriftsartikel (refereegranskat)abstract
- Intellectual disability (ID) occurs in almost 3% of newborns. Despite substantial research, a fundamental question about its origin and links to intelligence (IQ) still remains. ID has been shown to be inherited and has been accepted as the extreme low of the normal IQ distribution. However, ID displays a complex pattern of inheritance. Previously, noninherited rare mutations were shown to contribute to severe ID risk in individual families, but in the majority of cases causes remain unknown. Common variants associated with ID risk in the population have not been systematically established. Here we evaluate the hypothesis, originally proposed almost 1 century ago, that most ID is caused by the same genetic and environmental influences responsible for the normal distribution of IQ, but that severe ID is not. We studied more than 1,000,000 sibling pairs and 9,000 twin pairs assessed for IQ and for the presence of ID. We evaluated whether genetic and environmental influences at the extremes of the distribution are different from those operating in the normal range. Here we show that factors influencing mild ID (lowest 3% of IQ distribution) were similar to those influencing IQ in the normal range. In contrast, the factors influencing severe ID (lowest 0.5% of IQ distribution) differ from those influencing mild ID or IQ scores in the normal range. Taken together, our results suggest that most severe ID is a distinct condition, qualitatively different from the preponderance of ID, which, in turn, represents the low extreme of the normal distribution of intelligence.
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| 7. |
- Rischer, Heiko, et al.
(författare)
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Gene-to-metabolite networks for terpenoid indole alkaloid biosynthesis in Catharanthus roseus cells
- 2006
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 103:14, s. 5614-5619
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Tidskriftsartikel (refereegranskat)abstract
- Rational engineering of complicated metabolic networks involved in the production of biologically active plant compounds has been greatly impeded by our poor understanding of the regulatory and metabolic pathways underlying the biosynthesis of these compounds. Whereas comprehensive genome-wide functional genomics approaches can be successfully applied to analyze a select number of model plants, these holistic approaches are not yet available for the study of nonmodel plants that include most, if not all, medicinal plants. We report here a comprehensive profiling analysis of the Madagascar periwinkle (Catharanthus roseus), a source of the anticancer drugs vinblastine and vincristine. Genome-wide transcript profiling by cDNA-amplified fragment-length polymorphism combined with metabolic profiling of elicited C. roseus cell cultures yielded a collection of known and previously undescribed transcript tags and metabolites associated with terpenoid indole alkaloids. Previously undescribed gene-to-gene and gene-to-metabolite networks were drawn up by searching for correlations between the expression profiles of 417 gene tags and the accumulation profiles of 178 metabolite peaks. These networks revealed that the different branches of terpenoid indole alkaloid biosynthesis and various other metabolic pathways are subject to differing hormonal regulation. These networks also served to identify a select number of genes and metabolites likely to be involved in the biosynthesis of terpenoid indole alkaloids. This study provides the basis for a better understanding of periwinkle secondary metabolism and increases the practical potential of metabolic engineering of this important medicinal plant.
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| 8. |
- Sebastián, David, et al.
(författare)
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Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:14, s. 5523-5528
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria are dynamic organelles that play a key role in energy conversion. Optimal mitochondrial function is ensured by a quality-control system tightly coupled to fusion and fission. In this connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Here, we provide in vivo evidence that Mfn2 plays an essential role in metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to numerous metabolic abnormalities, characterized by glucose intolerance and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin signaling in liver and muscle. Furthermore, Mfn2 deficiency was associated with endoplasmic reticulum stress, enhanced hydrogen peroxide concentration, altered reactive oxygen species handling, and active JNK. Chemical chaperones or the antioxidant N-acetylcysteine ameliorated glucose tolerance and insulin signaling in liver-specific Mfn2 KO mice. This study provides an important description of a unique unexpected role of Mfn2 coordinating mitochondria and endoplasmic reticulum function, leading to modulation of insulin signaling and glucose homeostasis in vivo.
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| 9. |
- Tobe, Brian T. D., et al.
(författare)
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Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington DC, USA : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:22, s. E4462-E4471
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Tidskriftsartikel (refereegranskat)abstract
- The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active non-phosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2: CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the " lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.
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| 10. |
- van Baarlen, Peter, et al.
(författare)
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Differential NF-κB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington, DC : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:7, s. 2371-2376
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Tidskriftsartikel (refereegranskat)abstract
- How do we acquire immune tolerance against food microorganisms and commensal bacteria that constitute the intestinal microbiota? We investigated this by stimulating the immune system of adults with commensal Lactobacillus plantarum bacteria. We studied the in vivo human responses to L. plantarum in a randomized double-blind placebo-controlled cross-over study. Healthy adults ingested preparations of living and heat-killed L. plantarum bacteria. Biopsies were taken from the intestinal duodenal mucosa and altered expression profiles were analyzed using whole-genome microarrays and by biological pathway reconstructions. Expression profiles of human mucosa displayed striking differences in modulation of NF-kappaB-dependent pathways, notably after consumption of living L. plantarum bacteria in different growth phases. Our in vivo study identified mucosal gene expression patterns and cellular pathways that correlated with the establishment of immune tolerance in healthy adults.
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