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PubMed2026

Decoupled Synthesis Pathway via Precursor Functionalization Stabilizes High-Voltage Nickel-Based Cathodes.

Nickel-based layered cathodes are promising candidates for high-performance, high-energy lithium-ion batteries, yet their high-voltage application is jointly limited by synthesis-inherited structural defects and an unstable lattice oxygen framework. Here, we show that both limitations can be overcome by decoupled synthesis pathway (DSP) via La/Nb oxalate functionalization of the Ni0.6Co0.1Mn0.3(OH)2 precursor. Unlike the conventional coupled synthesis pathway (CSP) where precursor dehydration and Li2CO3 decomposition overlap in temperature, the DSP introduces a low‑temperature decomposition of La/Nb oxalates at 200°C, which effectively avoids localized contact between the precursor and Li2CO3 and shifts Li2CO3-related reactions to high temperatures. This allows sequential precursor dehydroxylation, rock‑salt (RS) intermediate formation, and layered‑phase transformation over a broad temperature window. The resulting LiNi0.6Co0.1Mn0.3O2 cathode with La/Nb functionalization (NCM-LN) features a uniform surface LaNiO3 perovskite heterostructure and a Nb‑doped layered bulk with suppressed RS and spinel defects. Consequently, under 4.5 V operation (vs. Li+/Li), NCM-LN exhibits homogeneous Li+ (de)intercalation, and a stabilized oxygen framework. In graphite||NCM-LN full cells, NCM-LN retains 80.1% of its capacity after 2000 cycles at 1C, substantially outperforming the pristine cathode. This decoupling strategy is broadly effective across various Ni‑based systems, providing a generalizable route toward high‑energy, long‑life cathode materials.

decoupled synthesis pathway↗

PubMed2005

Dietary phytoestrogens: potential selective estrogen enzyme modulators?

Between one-third to one-half of all breast cancers are steroid sensitive. Steroid-pathway enzymes (sulfatase, 17beta-hydroxysteroid dehydrogenases, aromatase and sulfotransferases) are thus prime candidates for therapeutic approaches based on the control of intacrine activity. Some phytoestrogens, ubiquitous in our diet, are inhibitors of these enzymes. Such a therapeutic potential has stimulated research and progress has been achieved during the last years. Complementary to previous reviews on phytoestrogens, this contribution covers the estrogen pathway inhibition effects of these compounds and special attention will be given to isoflavonoids, flavonoids and lignans. Furthermore, the research on structurally-related compounds as therapeutic agents will be discussed briefly.

Breast Neoplasms↗

PubMed1989

Pumps and pathways for gastric HCl secretion.

Data reviewed herein show that the HCl-secreting parietal cell is an exaggerated example of dynamic membrane transformation. Recruitment and recycling of membrane provide the means for the massive redistribution of the gastric proton pump, the H,K-ATPase, from one membrane domain (cytoplasmic tubulovesicles) to another (apical plasma membrane) as a function of parietal cell activation and inactivation. Functional activation of HCl secretion requires not only the redistribution of pump protein, but also the participation of pathways for the rapid flux of K+ and Cl- across the apical membrane. In apical plasma membrane vesicles from stimulated cells these pathways appear to be conductive and can operate independently. Thus, our model for the parietal cell proposes that K+ and Cl- flux from cell to lumen, operating in parallel and in concert with ATP-driven H+/K+ exchange, provides the concentration and osmotic forces required for net HCl secretion. Whether and how the K+ and Cl- pathways are activated by stimulation and/or how they get to the apical membrane domain remain important questions. With respect to mechanisms of parietal cell activation, secretagogue-coupled elevation of cAMP and activation of protein kinase A form the basis of a well-established second messenger pathway. Several laboratories have identified various proteins that are phosphorylated concomitant with parietal cell stimulation, representing numerous candidates for effectors in stimulus-secretion coupling. Here, we emphasized the possible involvement of an 80-kDa protein whose phosphorylation was correlated with the cAMP pathway of HCl secretion. Immunocytolocalization of the 80-kDa phosphoprotein to the apical membrane and associated actin microfilaments prompted our suggestion that this protein might serve as a linkage between plasma membrane and cytoskeleton. Search for a possible role for the 80-kDa phosphoprotein in apical surface organization, stability, and turnover should represent an important thrust of research. Further understanding of the mechanism of cell activation will require a more complete elaboration of the functional role of many activation-related proteins.

Adenosine Triphosphatases↗

PubMed2002

Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice.

Mice heterozygous for the Otx2 mutation display a craniofacial malformation, known as otocephaly or agnathia-holoprosencephaly complex. The severity of the phenotype is dependent on the genetic background of a C57BL/6 (B6) strain; most of the offspring of Otx2 knock-out chimeras, which are equivalent to the F(1) of CBA and B6 strains, backcrossed with B6 females display reduction or loss of mandible, whereas those backcrossed with CBA females do not show noticeable phenotype at birth. The availability of phenotypically disparate strains renders identification of Otx2 modifier loci possible. In this study, a backcross of chimera with B6 was generated and genome-wide scans were conducted with polymorphic markers for non-mendelian distribution of alleles in Otx2 heterozygous mutant mice displaying abnormalities in the lower jaw. We identified one significant locus, Otmf18, between D18Mit68 and D18Mit120 on chromosomes 18, linked to the mandibular phenotype (LOD score 3.33). A similar replication experiment using a second backcross (N3) mouse demonstrated the presence of another significant locus, Otmf2 between D2Mit164 and D2Mit282 on chromosome 2, linked to the mandibular phenotype (LOD score 3.93). These two modifiers account for the distribution of the craniofacial malformations by the genetic effect between B6 and CBA strains. Moreover, Otmf2 contain a candidate gene for several diseases in mice and humans. These genetic studies involving an otocephalic mouse model appear to provide new insights into mechanistic pathways of craniofacial development. Furthermore, these experiments offer a powerful approach with respect to identification and characterization of candidate genes that may contribute to human agnathia-holoprosencephaly complex diseases.

Animals↗

PubMed2006

Octahedral Pt(IV) complex K101 induces apoptosis via ERK1/2 activation and the p53 pathway in human colon cancer cells.

Recently, the synthesized octahedral Pt(IV) compound trans,cis-Pt(acetato)2Cl2(1,4-butanediamine), K101, showed potent anti-tumor activity in vitro and in vivo. For the further investigation of K101-induced anti-cancer activity, we tested cytotoxicity against various cancer cell lines and performed the histoculture drug response assay (HDRA) against human colorectal tumor tissues in vitro. We investigated the signaling pathway of K101-induced apoptosis via expression of p53 and ERK1/2 in the human colon cell line HCT116. The cytotoxicity and the three-dimensional HDRA of K101 were evaluated using the MTT assay. To study the K101-induced apoptosis pathway, we performed FACS analysis and immunoblotting of p53, p21, Bax, Fas and ERK1/2 in HCT116 cells treated with or without K101. The cytotoxic IC50 values of K101 ranged from 1.15 to 2.38 micromol/l, compared to cisplatin ranging from 2.13 to 13.1 micromol/l. Among several cancer cell lines, K101 showed greater potency than cisplatin in colon cancer cell lines. In the HDRA, K101 showed 80.0-91.4% efficacy rates compared with 48.6% for cisplatin against colorectal cancer patient tissues. In the signaling pathway, the expression of p53 and phospho-ERK1/2 was increased in a time-dependent manner by treatment with K101 in the HCT116 cells. When K101 was treated with MEK inhibitor U0126, the cell death rate was increased. The octahedral Pt(IV) complex K101 could be an attractive candidate as a chemotherapeutic agent against colon cancer. ERK1/2 activation and the p53 pathway may play significant functions in mediating K101-induced apoptosis in human colon cancer cells.

Antineoplastic Agents↗

PubMed2006

The mechanisms of vitamin K2-induced apoptosis of myeloma cells.

BACKGROUND AND OBJECTIVES: Physiologically, vitamin K compounds act as co-factors for g-carboxylation of selected glutamates at the N-terminus of prothrombin and some other coagulation factors. These congeners have some growth inhibitory effects of human neoplastic cells. Furthermore, vitamin K2 (VK2) cause apoptosis of some leukemic cells. In search for a new candidate agent to use in the maintenance treatment of myeloma, we analyzed the growth inhibitory effects and apoptosis-inducing capacity of VK2 in human myeloma cells. DESIGN AND METHODS: The growth of myeloma, lymphoma and non-lymphoid cells cultured with various concentrations of VK2 with or without dexamethasone or allopurinol was assayed. Flow cytometry was used to detect apoptotic cells, activated caspase-3 and -9, the generation of superoxide by hydroethidine, and mitochondrial membrane potential (E centym). In addition, the activation of apoptosis-inducing MAPK, p38 and JNK, release of cytochrome c from mitochondria, and change in the relative Bcl-XL/Xs expression balance were analyzed by Western blotting. RESULTS: Myeloma cells and B-cell lymphoma cells were sensitive to VK2. The growth inhibition was caused by apoptosis and activation of caspase-3. The generation of superoxide, and inhibitory effects of the xanthine oxidase inhibitor allopurinol, were demonstrated in myeloma cells. The phosphorylation of MAPK was increased by VK2 in myeloma cells. In addition, the mitochondrial apoptotic pathway was activated. INTERPRETATION AND CONCLUSIONS: VK2 may be a good candidate for myeloma patients, particularly patients who are not suitable candidates for intensive cytoreductive chemotherapy due to age and/or complications.

Allopurinol↗

PubMed2006

Structural and mechanistic features of protein O glycosylation linked to CD8+ T-cell apoptosis.

CD8+ T-cell apoptosis is essential for the contraction phase of the immune response, yet the initiating signals and precise pathways involved are unresolved. The ST3Gal-I sialyltransferase is a candidate mechanistic component and catalyzes sialic acid addition to core 1 O-glycans during protein O glycosylation. ST3Gal-I inactivation or enzymatic removal of its product renders CD8+ T cells, but not CD4+ T cells, susceptible to apoptosis by differential cross-linking of O-glycoproteins in the absence of interleukin-2 and T-cell receptor (TCR) signaling. This results in caspase activation, DNA fragmentation, and phosphatidylserine externalization prior to cell death. We further show that ST3Gal-I function is regulated by a posttranscriptional mechanism operating distal to Golgi core 2 O glycosylation and is invariably linked to CD8+ T-cell contraction following viral (lymphocytic choriomeningitis virus) infection and bacterial (staphylococcal enterotoxin B) antigen immunization. The mechanism does not involve the ST3Gal-I substrate CD43 or core 2 O-glycan induction and overcomes the ability of Bcl-2 to inhibit the contraction phase in vivo. Loss of ST3Gal-I function further reduces Bim-deficient CD8+ T-cell accumulation without diminishing apoptotic sensitivity. We propose that an endogenous lectin activates an apoptotic pathway constructed in CD8+ T cells following TCR stimulation and enables contraction upon attenuation of immune signaling.

Animals↗

PubMed2001

The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.

When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.

Alleles↗

PubMed2003

QTL and candidate genes phytoene synthase and zeta-carotene desaturase associated with the accumulation of carotenoids in maize.

Carotenoids are a class of fat-soluble antioxidant vitamin compounds present in maize ( Zea mays L.) that may provide health benefits to animals or humans. Four carotenoid compounds are predominant in maize grain: beta-carotene, beta-cryptoxanthin, zeaxanthin, and lutein. Although beta-carotene has the highest pro-vitamin A activity, it is present in a relatively low concentration in maize kernels. We set out to identify quantitative trait loci (QTL) affecting carotenoid accumulation in maize kernels. Two sets of segregating families were evaluated-a set of F2:3 lines derived from a cross of W64a x A632, and their testcross progeny with AE335. Molecular markers were evaluated on the F2:3 lines and a genetic linkage map created. High-performance liquid chromatography was performed to measure beta-carotene, beta-cryptoxanthin, zeaxanthin, and lutein on both sets of materials. Composite interval mapping identified chromosome regions with QTL for one or more individual carotenoids in the per se and testcross progenies. Notably QTL in the per se population map to regions with candidate genes, yellow 1 and viviparous 9, which may be responsible for quantitative variation in carotenoids. The yellow 1 gene maps to chromosome six and is associated with phytoene synthase, the enzyme catalyzing the first dedicated step in the carotenoid biosynthetic pathway. The viviparous 9 gene maps to chromosome seven and is associated with zeta-carotene desaturase, an enzyme catalyzing an early step in the carotenoid biosynthetic pathway. If the QTL identified in this study are confirmed, particularly those associated with candidates genes, they could be used in an efficient marker-assisted selection program to facilitate increasing levels of carotenoids in maize grain.

Alkyl and Aryl Transferases↗

PubMed2006

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample.

Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3'UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.

Adult↗

PubMed2006

Gene expression profiles in mouse urethral development.

OBJECTIVE: To analyse the gene expression profiles of the mouse genital tubercle (GT) during urethral tube development at embryonic (E) days E14, E15, E16 and E17, as the aetiology of hypospadias, one of the most common congenital anomalies, remains unknown. MATERIALS AND METHODS: During GT development the urethral folds fuse to form an epithelial seam; subsequently, the epithelial seam disappears, resulting in the normal tubular urethra. Abnormalities in urethral seam formation and remodelling might explain hypospadias, and elucidating the molecular developmental mechanisms underlying normal penile development might provide the basis for understanding hypospadias. Total RNA was isolated from the genital tubercle at embryonic days E14, E15, E16, and E17. Together with reference RNA, sample RNA was labelled with Cy-3 and Cy-5 respectively and hybridized to a 16 000-mouse gene array that included the Incyte GEM2.1 and NIA 7k sets. Candidate genes were analysed by immunohistochemistry and real-time polymerase chain reaction. RESULTS: Using cDNA microarrays, we identified the up-regulation of genes involved in the transforming growth factor (TGF)-beta and Wnt-Frizzled pathways, and of thrombospondin (TSP) 4, a member of a cell-migration molecule family, all candidates for involvement in urethral tube formation. Immunohistochemistry showed TGFbeta1, TGFbeta receptor III, and Frizzled1 were expressed exclusively in E14-E17 urethral epithelium. TSP4 was expressed in the mesenchymal basal layer underlying E17 GT skin epidermis. CONCLUSIONS: Many signalling pathways are involved in late GT development, and cell migration molecules might have an important role in urethral tube formation.

Animals↗

PubMed2006

p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans.

The PMK-1 p38 mitogen-activated protein kinase pathway and the DAF-2-DAF-16 insulin signaling pathway control Caenorhabditis elegans intestinal innate immunity. pmk-1 loss-of-function mutants have enhanced sensitivity to pathogens, while daf-2 loss-of-function mutants have enhanced resistance to pathogens that requires upregulation of the DAF-16 transcription factor. We used genetic analysis to show that the pathogen resistance of daf-2 mutants also requires PMK-1. However, genome-wide microarray analysis indicated that there was essentially no overlap between genes positively regulated by PMK-1 and DAF-16, suggesting that they form parallel pathways to promote immunity. We found that PMK-1 controls expression of candidate secreted antimicrobials, including C-type lectins, ShK toxins, and CUB-like genes. Microarray analysis demonstrated that 25% of PMK-1 positively regulated genes are induced by Pseudomonas aeruginosa infection. Using quantitative PCR, we showed that PMK-1 regulates both basal and infection-induced expression of pathogen response genes, while DAF-16 does not. Finally, we used genetic analysis to show that PMK-1 contributes to the enhanced longevity of daf-2 mutants. We propose that the PMK-1 pathway is a specific, indispensable immunity pathway that mediates expression of secreted immune response genes, while the DAF-2-DAF-16 pathway appears to regulate immunity as part of a more general stress response. The contribution of the PMK-1 pathway to the enhanced lifespan of daf-2 mutants suggests that innate immunity is an important determinant of longevity.

Animals↗

PubMed2026

The Multi-Omics Landscape of Enzymatic Alterations in Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease closely associated with enzyme dysfunction, yet its underlying molecular mechanisms remain incompletely understood. This study aims to characterize enzyme-network alterations associated with SLE status and disease activity and to identify candidate molecules with potential clinical relevance. METHODS: We integrated proteomic and phosphoproteomic data from peripheral blood mononuclear cells (PBMCs) of 130 SLE patients and 90 healthy controls (HC), along with transcriptomic data from 1461 SLE patients. Through systematic analysis of key enzyme phosphorylation sites, upstream transcription factors (TFs), and computationally prioritized candidate compounds, we sought to characterize enzyme-centered regulatory associations. RESULTS: Integrated proteomic and phosphoproteomic analyses revealed significant metabolic and signaling pathway disturbances, along with distinct phosphorylation patterns in SLE immune cells. Multiple SLE-associated and disease-activity-associated candidate molecules were identified. Regulatory network analysis uncovered an upstream transcription factor cluster centered around STAT1. Computational drug screening identified computationally prioritized candidate compounds with multi-gene DSigDB associations, which require further clinical safety evaluation and experimental validation. CONCLUSIONS: This study constructs a molecular map of SLE, highlighting associations between enzyme-network alterations, catalytic dysregulation, and SLE-related immune molecular signatures, and identifies candidate molecules for future clinical and functional evaluation.

Humans↗

PubMed1996

Neo-Darwinian developmental evolution: can we bridge the gap between pattern and process?

In the past decade, there has been a surge of renewed interest in the study of developmental evolution. One approach that has been taken is to examine the expression patterns of a candidate gene in divergent taxa and to use these results to infer which aspects of a particular genetic pathway are either conserved or altered. Here we consider this approach from the perspective of the neo-Darwinian paradigm for evolutionary change. If adaptations are typically composed of large numbers of gene substitutions that are of small effect individually, then the candidate gene approach is unlikely to bridge the gap between developmental pattern and evolutionary process: changes in gene expression patterns may identify the steps in developmental pathways that have been altered during evolution but fail to identify the actual genetic changes that have occurred. On the other hand, there is growing support for the view that adaptations often involve large-effect genes; fortunately, the candidate gene approach is well suited to this type of genetic architecture.

Animals↗

PubMed2004

Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium.

BACKGROUND: Gene expression technologies have the ability to generate vast amounts of data, yet there often resides only limited resources for subsequent validation studies. This necessitates the ability to perform sorting and prioritization of the output data. Previously described methodologies have used functional pathways or transcriptional regulatory grouping to sort genes for further study. In this paper we demonstrate a comparative genomics based method to leverage data from animal models to prioritize genes for validation. This approach allows one to develop a disease-based focus for the prioritization of gene data, a process that is essential for systems that lack significant functional pathway data yet have defined animal models. This method is made possible through the use of highly controlled spotted cDNA slide production and the use of comparative bioinformatics databases without the use of cross-species slide hybridizations. RESULTS: Using gene expression profiling we have demonstrated a similar whole transcriptome gene expression patterns in prostate cancer cells from human and rat prostate cancer cell lines both at baseline expression levels and after treatment with physiologic concentrations of the proposed chemopreventive agent Selenium. Using both the human PC3 and rat PAII prostate cancer cell lines have gone on to identify a subset of one hundred and fifty-four genes that demonstrate a similar level of differential expression to Selenium treatment in both species. Further analysis and data mining for two genes, the Insulin like Growth Factor Binding protein 3, and Retinoic X Receptor alpha, demonstrates an association with prostate cancer, functional pathway links, and protein-protein interactions that make these genes prime candidates for explaining the mechanism of Selenium's chemopreventive effect in prostate cancer. These genes are subsequently validated by western blots showing Selenium based induction and using tissue microarrays to demonstrate a significant association between downregulated protein expression and tumorigenesis, a process that is the reverse of what is seen in the presence of Selenium. CONCLUSIONS: Thus the outlined process demonstrates similar baseline and selenium induced gene expression profiles between rat and human prostate cancers, and provides a method for identifying testable functional pathways for the action of Selenium's chemopreventive properties in prostate cancer.

Adenocarcinoma↗

PubMed2003

Modulation of perch connexin35 hemi-channels by cyclic AMP requires a protein kinase A phosphorylation site.

Retinal neurons are coupled via gap junctions, which function as electrical synapses that are gated by ambient light conditions. Gap junctions connecting either horizontal cells or AII amacrine cells are inhibited by the neurotransmitter dopamine, via the activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. Fish connexin35 (Cx35) and its mouse ortholog, Cx36, are good candidates to undergo dopaminergic modulation, because they have been detected in the inner plexiform layer of the retina, where Type II amacrine cells establish synaptic contacts. We have taken advantage of the ability of certain connexins to form functional connexons (hemi-channels), when expressed in Xenopus oocytes, to investigate whether pharmacological elevation of cAMP modulates voltage-activated hemi-channel currents in single oocytes. Injection of perch Cx35 RNA into Xenopus oocytes induced outward voltage-dependent currents that were recorded at positive membrane potentials. Incubation of oocytes with 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), a membrane permeable cAMP analog, resulted in a dose-dependent and reversible inhibition of hemi-channel currents at the more positive voltage steps. In contrast, treatment with 8-Br-cAMP did not have any effect on hemi-channel currents induced by skate Cx35. Amino acid sequence comparison of the two fish connexins revealed, in the middle cytoplasmic loop of perch Cx35, the presence of a PKA consensus sequence that was absent in the skate connexin. The results obtained with two constructs in which the putative PKA phosphorylation site was either suppressed (perch Cx35R108Q) or introduced (skate Cx35Q108R) indicate that it is responsible for the inhibition of hemi-channel currents. These studies demonstrate that perch Cx35 is a target of the cAMP/PKA signaling pathway and identify a consensus PKA phosphorylation site that is required for channel gating.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2026

Type I Interferon Signature is Associated With Lung Disease, Drug-Associated Immune Reactions, and Genetic Variation in Interferon-Linked Pathways in Still Disease.

OBJECTIVE: To evaluate the relationship across type I interferon (IFN-I)-stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to interleukin-1 (IL-1) and/or IL-6 inhibitors. METHODS: Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still or Still-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. RESULTS: Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs 0.1, P = 0.007) and DAIR (0.63 vs 0.17, P = 0.003) and lower IL-6 inhibitor use (0 vs 0.25, P = 0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in IFN-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization, and responses to stress. CONCLUSION: High IFN-I expression correlates with LD and DAIR in Still disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still disease with IFN-I signature.

Humans↗

PubMed2005

Unexpected behavior of coniferin in lignin biosynthesis of Ginkgo biloba L.

To gain insight into the behavior of monolignol glucoside in Ginkgo biloba L., we examined glucosides potentially involved in lignin biosynthetic pathway. Coniferin (coniferyl alcohol 4O-beta-D-glucoside) is a strong candidate for the storage form of monolignol. Coniferaldehyde glucoside may also have a role in lignin biosynthesis; this was examined with tracer experiments using labeled glucosides fed to stem segments. A series of tracer experiments showed that coniferin and coniferaldehyde glucoside were modified into coniferyl alcohol and then efficiently incorporated into lignin under the experimental conditions used. Interestingly, more than half of the administered coniferin underwent an oxidation to the aldehyde form before its aglycone; coniferyl alcohol was polymerized into lignin. This suggests that there is an alternative pathway for coniferin to enter the monolignol biosynthetic pathway, in addition to the direct pathway beginning with the deglucosylation of coniferin catalyzed by beta-glucosidase. Enzymatic assays revealed that coniferaldehyde glucoside was produced enzymatically from coniferin, and that coniferaldehyde glucoside can be deglucosylated to yield coniferaldehyde, which could be fated to become coniferyl alcohol . Albeit the findings cannot be taken as proof for the in-planta functioning, these results present a possibility for the existence of alternative pathway in which some of the stored coniferin is oxidized to coniferaldehyde glucoside, which is deglucosylated to generate coniferaldehyde that joins the monolignol biosynthesis pathway.

Cinnamates↗