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The identification of the bacterial endotoxin receptors for innate immunity, most notably TLR4 (Toll-like receptor 4), has sparked great interest in therapeutic manipulation of the innate immune system. In the present mini-review, several natural and synthetic molecules that modulate the TLR4-mediated LPS (lipopolysaccharide) signalling in animals and humans are considered, and their mechanisms of action are discussed. The process of LPS sensing and signal amplification in humans is based on the sequential action of specific receptors situated in the extracellular side of the innate immunity cells, which bind and transfer LPS to TLR4: LBP (LPS-binding protein), CD14, MD-2 (myeloid differentiation protein 2). We classified the compounds active on TLR4 pathway depending on the specific molecular targets (LPS, LBP, CD14, MD-2 or TLR4). Small molecules developed by our group are described that inhibit LPS-stimulated TLR4 activation by selectively targeting the LPS-CD14 interaction. These compounds ...

Toll-like receptors (TLRs) are evolutionarily conserved pattern-recognition molecules that recognize different microbial products during infection and serve as an important link between the innate and adaptive immune responses. The signaling of these TLRs is kept under tight control by the expression of endogenous inhibiting proteins such as RP105, a recently identified homolog of TLR4. This protein, in association with MD-1, interacts with and inhibits the TLR4/MD-2 signaling pathway.. While MD-2 can directly bind to LPS, one of the activating molecules of TLR4, the function of MD-1 is less well-known. It has been suggested however, that the RP105/MD-1 complex influences antibody production mediated by both TLR4/MD-2 and TLR2 receptor complexes. ...

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p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class=publication>Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href=http://www.nrbook.com/b/bookcpdf.php>Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...

Fluorescence microscopy revealed a punctuated pattern of TLR1 staining on monocytes derived from individuals who express surface TLR1 (Fig. 1⇑B, top left panel). Conversely, monocytes derived from donors who did not express surface TLR1 exhibited no detectable signal above that observed with an isotype control Ab (Fig. 1⇑B, top right panel). When cells were permeabilized before staining, intracellular TLR1 was detected in both groups in a diffuse pattern (Fig. 1⇑B, bottom panels). However, monocytes that lacked cell surface TLR1 exhibited a greater intensity of intracellular staining that was distributed predominantly within the perinuclear region of the cell (Fig. 1⇑B, bottom right panel). These results show that an inability to transport TLR1 to the cell surface underlies the deficiency in surface expression and suggests that instead the receptor accumulates within the cell, possibly within the endoplasmic reticulum or Golgi network.. Since no defect in surface expression of the ...

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Author Summary The outer leaflet of the outer membrane of Gram-negative bacteria is mainly composed of lipopolysaccharide (LPS, endotoxin). The structure of the bioactive component of LPS, lipid A, varies between bacteria and even within the same species grown under different environmental conditions. Yersinia pestis has been associated with highly lethal bubonic plagues of the past. It alters the structure of its LPS based on temperature. When grown at ambient temperatures comparable to fleas in temperate climates, the LPS is mainly hexa-acylated. However, upon growth at 37°C, the mammalian host temperature, Y. pestis switches to synthesize a hypo-acylated LPS that is less stimulatory to the human compared with murine LPS receptor complex composed of Toll-like receptor (TLR) 4 and MD-2. To test whether the change in LPS structure associated with replication at mammalian temperature promotes Y. pestis virulence by evading recognition by the human receptor complex, we generated

Despite considerable therapeutic potential of stimulatory ODNs, their application in the therapy and identification of several types of ODNs, the rational design of TLR9 agonists has been limited by a lack of clear information on the structural parameters that define the minimal ligand features required for the TLR9 activation. This changed recently by the determination of the crystal structures of horse and mouse TLR9 with bound B class short ODNs (7). This structure pointed to the recognition of a single CpG by the receptor, although our previous study identified a clear requirement for a pair of CpG required for the activation of hTLR9. Although the CpG motif represents the consensus recognition motif of all TLR9, its sequence selectivity is species-specific (1, 8-12). In this paper, we identified the minimal sequence motifs of ODNs for the effective and specific activation of mouse receptor. In summary, the minM may be defined by the sequence pattern [T]4-6CG[T]12-21. However, the activation ...

Amps K, Andrews PW, Anyfantis G, Armstrong L, Avery S, Baharvand H, Baker J, Baker D, Munoz MB, Beil S, Benvenisty N, Ben-Yosef D, Biancotti JC, Bosman A, Brena RM, Brison D, Caisander G, Camarasa MV, Chen J, Chiao E, Choi YM, Choo AB, Collins D, Colman A, Crook JM, Daley GQ, Dalton A, De Sousa PA, Denning C, Downie J, Dvorak P, Montgomery KD, Feki A, Ford A, Fox V, Fraga AM, Frumkin T, Ge L, Gokhale PJ, Golan-Lev T, Gourabi H, Gropp M, Lu G, Hampl A, Harron K, Healy L, Herath W, Holm F, Hovatta O, Hyllner J, Inamdar MS, Irwanto AK, Ishii T, Jaconi M, Jin Y, Kimber S, Kiselev S, Knowles BB, Kopper O, Kukharenko V, Kuliev A, Lagarkova MA, Laird PW, Lako M, Laslett AL, Lavon N, Lee DR, Lee JE, Li C, Lim LS, Ludwig TE, Ma Y, Maltby E, Mateizel I, Mayshar Y, Mileikovsky M, Minger SL, Miyazaki T, Moon SY, Moore H, Mummery C, Nagy A, Nakatsuji N, Narwani K, Oh SK, Oh SK, Olson C, Otonkoski T, Pan F, Park IH, Pells S, Pera MF, Pereira LV, Qi O, Raj GS, Reubinoff B, Robins A, Robson P, Rossant J, ...

Beutler is best known for his pioneering molecular and genetic studies of inflammation and innate immunity. Interested in the mechanism by which lipopolysacchride (LPS) activates mammalian immune cells, Beutler identified the LPS receptor. Identification of the receptor hinged on the positional cloning (a method of gene identification) of the mammalian Lps locus, which had been known since the 1960s as a key gene for biological responses to LPS.[4]. Beutler thus discovered the key sensors of microbial infection in mammals. He found that one of the mammalian toll-like receptors,[5] TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex.[6] The TLRs work in the perception of microbes. Ten are now known in humans. Each detects signature molecules produced early in an infection. These receptors also work in severe illness, including shock and systemic inflammation as it occurs in the course of an infection. They are also active in sterile inflammatory and autoimmune ...

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of HMGB1 and TLR4 results in upregulation of NF-kappa B, which leads to increased production and an release of cytokines in macrophages and in neutrophils for example stimulates ... HMGB1-LPS complex activates TLR4, and leads to binding adapter proteins (MyD88 and others), which leads to signal transduction and activate signaling cascades ... In the last line leads to activation of MAPK cascades and NF-kapa B and thus to the production of cytokines and other inflammatory molecules ...

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Richter J, Schlesner M, Hoffmann S, Kreuz M, Leich E, Burkhardt B, Rosolowski M, Ammerpohl O, Wagener R, Bernhart SH, Lenze D, Szczepanowski M, Paulsen M, Lipinski S, Russell RB, Adam-Klages S, Apic G, Claviez A, Hasenclever D, Hovestadt V, Hornig N, Korbel JO, Kube D, Langenberger D, Lawerenz C, Lisfeld J, Meyer K, Picelli S, Pischimarov J, Radlwimmer B, Rausch T, Rohde M, Schilhabel M, Scholtysik R, Spang R, Trautmann H, Zenz T, Borkhardt A, Drexler HG, Möller P, MacLeod RA, Pott C, Schreiber S, Trümper L, Loeffler M, Stadler PF, Lichter P, Eils R, Küppers R, Hummel M, Klapper W, Rosenstiel P, Rosenwald A, Brors B, Siebert R. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet. 2012 Dec; 44(12):1316-20 ...

p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class=publication>Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href=http://www.nrbook.com/b/bookcpdf.php>Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...

Clone REA599 recognizes the human CD14 antigen. CD14 is part of the functional heteromeric LPS receptor complex comprised of at least CD14, TLR4, and MD-2. It up-regulates cell surface molecules, including adhesion molecules. CD14 is strongly expressed on most human monocytes and macrophages in peripheral blood, other bodily fluids, and in various tissues such as lymph nodes and spleen. CD14 is weakly expressed on subpopulations of human neutrophils and myeloid dendritic cells.Additional information: Clone REA599 displays negligible binding to Fc receptors. - Nederland

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The freestanding neptunite crystal here is pristine, complete all around, and has excellent luster. It is just about 2 cm tall. Few neptunite crystals stand so nicely - most form lying upon the matrix and so it takes a trick of prepping the piece to make them look upright even when they are not. This one, its legitimately sticking up into what was a pocket. The cluster of benitoite at its base is an unusual offset and complement to the stark black neptunite. The larger benitoite is also 2 cm in size, across. The benitoites are not gemmy all through, but they are translucent and have reasonably good color as well. Ex. F. John Barlow Collection ...

Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead ...

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SPR reveals ColN‐R is responsible for LPS binding. Histidine‐tagged ColN domain combinations (500 nM) were injected for 60 s at a flow rate of 5 μl m

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為了解豬生殖與呼吸綜合症病毒ORF3蛋白之表現及性質，本研究將台灣分離株MD-001之ORF3基因構築於真核綠色螢光蛋白表現載體，以便追蹤ORF3綠色螢光融合蛋白的表現。結果顯示實驗組之ORF3綠色螢光蛋白只出現在細胞質，並有聚集在細胞一端的情況；而控制組之綠色螢光蛋白則均勻分佈於整個細胞。此外，實驗組表現之綠色螢光的細胞數量雖然不多，但其表現細胞卻多呈圓形化。以西方轉漬法可確認綠色螢光蛋白在控制組細胞內的表現，但是不管在細胞內或培養的上清液中皆無法偵測到ORF3綠色螢光蛋白。為瞭解此結果是否與表現量過低有關，進一步分析兩組細胞表現的綠色螢光蛋白mRNA，發現實驗組與控制組的基因表現量無明顯差異。未來需要設計不同實驗釐清上述現象是否為ORF3蛋白可能具有細胞毒性相關特性或是與綠色螢光蛋白融合所致

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Link to Pubmed [PMID] - 9301528. Immunology 1997 Jul;91(3):391-8. Although lipopolysaccharide (LPS)-induced overproduction of cytokines, involved in the pathogenesis of septic shock, occupies the spotlight of endotoxin research, another LPS effect, the differentiation of various cell types including haematopoietic bone marrow cells (BMC), which is probably related to its radioprotective activity, deserves equal attention. We have previously established that nanomolar concentrations of LPS trigger in human BMC the expression of CD14 by an induction mechanism independent of CD14 or any other molecule anchored to the cell membrane by a glycosyl phosphatidylinositol glycolipid. We now show that this LPS-induced stimulation is triggered by the binding of a small number of LPS molecules (13,000 molecules/cell) to constitutive LPS receptors of low affinity (Kd = 480 nM). This interaction, which was inhibited by a synthetic LPS antagonist, appeared specific, reversible, saturable, time- and ...

Here, we provided evidence that RP105/MD-1 plays a major role in regulating adipose tissue inflammation and metabolic disorders. Many detrimental consequences of an HFD were ameliorated by targeting genes encoding for RP105 or MD-1. TLR4 KO mice showed reduced HFD-induced adipose tissue inflammation (Fig. 6), but our results clearly revealed more requirements of RP105/MD-1 than TLR4/MD-2 in the induction of adipose tissue inflammation and obesity. The higher levels of cell surface and transcript expression of RP105/MD-1 in eWAT might simply reflect the requirements of RP105/MD-1 (Figs. 1-3). As is demonstrated, however, RP105/MD-1 plays unique, TLR4-independent roles in adipose tissue inflammation, and a ligand and signaling pathway of RP105/MD-1 must be different from those of TLR4/MD-2 (Fig. 8A and Supplementary Fig. 9). A dietary or endogenous ligand other than palmitic and stearic acids might trigger upregulation of RP105 on macrophages that, in turn, accumulate in adipose tissue. The ...

MCL1 Antibody is a Rabbit Polyclonal antibody against MCL1. This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cel

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TY - JOUR. T1 - Micrococci and peptidoglycan activate TLR2 →Myd88 →IRAK→TRAF→NIK→IKK→NF-κB signal transduction pathway that induces transcription of interleukin-8. AU - Wang, Q.. AU - Dziarski, R.. AU - Kirschning, C. J.. AU - Muzio, M.. AU - Gupta, D.. PY - 2001/4/5. Y1 - 2001/4/5. N2 - This study was done to elucidate the signal transduction pathway of interleukin-8 (IL-8) induction by gram-positive bacteria. Bacteria (micrococci) and peptidoglycan (PGN) induced transcription of IL-8 in HEK293 cells expressing Toll-like receptor 2 (TLR2) and CD14 but not in those expressing TLR1 or TLR4. A mutation within the NF-κB site in the IL-8 promoter abrogated transcriptional induction of IL-8 by the two stimulants. Dominant negative myeloid differentiation protein (MyD88), IL-1 receptor-associated kinase (IRAK), NFκB-inducing kinase (NIK), and IκB kinase (IKK) mutant forms completely inhibited micrococcus- and PGN-induced activation of NF-κB and expression of the gene for IL-8. ...

Clone TÜK4 recognizes the human CD14 antigen and cross-reacts with non-human primate CD14. The CD14 antigen is a high affinity receptor for lipopolysaccharides (LPS) and LPS-binding protein (LBP)-complexes. It is part of the functional heteromeric LPS receptor complex comprised of CD14, TLR4, and MD-2.CD14 is strongly expressed on most human monocytes and macrophages in peripheral blood, other body fluids, and various tissues, such as lymph nodes and spleen. CD14 is expressed at high levels, also on a few CD1c (BDCA-1)+ CD2+ myeloid dendritic cells and at low levels on neutrophilic granulocytes. Ex vivo differentiation of monocytes to dendritic cells is associated with down-regulation of CD14 antigen expression. - Lëtzebuerg

CD14 is a 55 kDa GPI-anchored glycoprotein, constitutively expressed on the surface of mature monocytes, macrophages, and neutrophils, where serves as a multifunctional lipopolysaccharide receptor; it is also released to the serum both as a secreted and enzymatically cleaved GPI-anchored form. CD14 binds lipopolysaccharide molecule in a reaction catalyzed by lipopolysaccharide-binding protein (LBP), an acute phase serum protein. The soluble sCD14 is able to discriminate slight structural differences between lipopolysaccharides and is important for neutralization of serum allochthonous lipopolysaccharides by reconstituted lipoprotein particles. CD14 affects allergic, inflammatory and infectious processes ...

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You are viewing an interactive 3D depiction of the molecule (4ar,10ar)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,8-diol (C13H17NO2) from the PQR.

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