Статті в журналах: "AP-4 Complex"

1

Hirst, Jennifer, Nicholas A. Bright, Brian Rous, and Margaret S. Robinson. "Characterization of a Fourth Adaptor-related Protein Complex." Molecular Biology of the Cell 10, no. 8 (August 1999): 2787–802. http://dx.doi.org/10.1091/mbc.10.8.2787.

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Adaptor protein complexes (APs) function as vesicle coat components in different membrane traffic pathways; however, there are a number of pathways for which there is still no candidate coat. To find novel coat components related to AP complexes, we have searched the expressed sequence tag database and have identified, cloned, and sequenced a new member of each of the four AP subunit families. We have shown by a combination of coimmunoprecipitation and yeast two-hybrid analysis that these four proteins (ε, β4, μ4, and ς4) are components of a novel adaptor-like heterotetrameric complex, which we are calling AP-4. Immunofluorescence reveals that AP-4 is localized to ∼10–20 discrete dots in the perinuclear region of the cell. This pattern is disrupted by treating the cells with brefeldin A, indicating that, like other coat proteins, the association of AP-4 with membranes is regulated by the small GTPase ARF. Immunogold electron microscopy indicates that AP-4 is associated with nonclathrin-coated vesicles in the region of the trans-Golgi network. The μ4 subunit of the complex specifically interacts with a tyrosine-based sorting signal, indicating that, like the other three AP complexes, AP-4 is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs. AP-4 is of relatively low abundance, but it is expressed ubiquitously, suggesting that it participates in a specialized trafficking pathway but one that is required in all cell types.

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2

Salazar, G., B. Craige, M. L. Styers, K. A. Newell-Litwa, M. M. Doucette, B. H. Wainer, J. M. Falcon-Perez, et al. "BLOC-1 Complex Deficiency Alters the Targeting of Adaptor Protein Complex-3 Cargoes." Molecular Biology of the Cell 17, no. 9 (September 2006): 4014–26. http://dx.doi.org/10.1091/mbc.e06-02-0103.

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Mutational analyses have revealed many genes that are required for proper biogenesis of lysosomes and lysosome-related organelles. The proteins encoded by these genes assemble into five distinct complexes (AP-3, BLOC-1-3, and HOPS) that either sort membrane proteins or interact with SNAREs. Several of these seemingly distinct complexes cause similar phenotypic defects when they are rendered defective by mutation, but the underlying cellular mechanism is not understood. Here, we show that the BLOC-1 complex resides on microvesicles that also contain AP-3 subunits and membrane proteins that are known AP-3 cargoes. Mouse mutants that cause BLOC-1 or AP-3 deficiencies affected the targeting of LAMP1, phosphatidylinositol-4-kinase type II alpha, and VAMP7-TI. VAMP7-TI is an R-SNARE involved in vesicle fusion with late endosomes/lysosomes, and its cellular levels were selectively decreased in cells that were either AP-3- or BLOC-1–deficient. Furthermore, BLOC-1 deficiency selectively altered the subcellular distribution of VAMP7-TI cognate SNAREs. These results indicate that the BLOC-1 and AP-3 protein complexes affect the targeting of SNARE and non-SNARE AP-3 cargoes and suggest a function of the BLOC-1 complex in membrane protein sorting.

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3

Dell’Angelica, Esteban C., Chris Mullins, and Juan S. Bonifacino. "AP-4, a Novel Protein Complex Related to Clathrin Adaptors." Journal of Biological Chemistry 274, no. 11 (March 12, 1999): 7278–85. http://dx.doi.org/10.1074/jbc.274.11.7278.

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4

Ponsankarar, Lalitha, A. Sinthiya, and V. Rashmi. "Hydrogen-bonding interaction of 4-AP metal complex with proteins." Acta Crystallographica Section A Foundations and Advances 73, a2 (December 1, 2017): C402. http://dx.doi.org/10.1107/s2053273317091719.

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5

Behne, Robert, Julian Teinert, Miriam Wimmer, Angelica D’Amore, Alexandra K. Davies, Joseph M. Scarrott, Kathrin Eberhardt, et al. "Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking." Human Molecular Genetics 29, no. 2 (January 9, 2020): 320–34. http://dx.doi.org/10.1093/hmg/ddz310.

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Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

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6

BAROIS, Nicolas, and Oddmund BAKKE. "The adaptor protein AP-4 as a component of the clathrin coat machinery: a morphological study." Biochemical Journal 385, no. 2 (January 7, 2005): 503–10. http://dx.doi.org/10.1042/bj20041010.

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The four members of the AP (adaptor protein) family are heterotetrameric cytosolic complexes that are involved in the intracellular trafficking of cargo proteins between different organelles. They interact with motifs present in the cytoplasmic tails of their specific cargo proteins at different intracellular locations. While AP-1, AP-2 and AP-3 have been investigated extensively, very few studies have focused on the fourth member, AP-4. In the present study, we report on the intracellular localization of AP-4 in the MDCK (Madin–Darby canine kidney) and MelJuSo cell lines after immunogold labelling of ultrathin cryosections. We find that AP-4 is localized mainly in the Golgi complex, as well as on endosomes and transport vesicles. Interestingly, we show for the first time that AP-4 is localized with the clathrin coat machinery in the Golgi complex and in the endocytic pathway. Furthermore, we find that AP-4 is localized with the CI-MPR (cation-independent mannose 6-phosphate receptor), but not with the transferrin receptor, LAMP-2 (lysosomal-associated membrane protein-2) or invariant chain. The difference in morphology between CI-MPR/AP-4-positive vesicles and CI-MPR/AP-1-positive vesicles raises the possibility that AP-4 acts at a location different from that of AP-1 in the intracellular trafficking pathway of CI-MPR.

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7

Mattera, Rafael, Chad D. Williamson, Xuefeng Ren, and Juan S. Bonifacino. "The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A." Molecular Biology of the Cell 31, no. 9 (April 15, 2020): 963–79. http://dx.doi.org/10.1091/mbc.e19-11-0658.

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In this study, we identify the dynein–dynactin adaptor FTS-Hook-FHIP (FHF) complex as an accessory factor for the TGN-associated adaptor protein 4 (AP-4) coat. We show that FHF is required for distribution of AP-4 and its cargo ATG9A to the perinuclear area, highlighting a novel mechanism for coupling of transport vesicles to microtubule motors.

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8

Schneider, Helga, Margarita Martin, Fernando A. Agarraberes, Li Yin, Iris Rapoport, Tomas Kirchhausen та Christopher E. Rudd. "Cytolytic T Lymphocyte-Associated Antigen-4 and the TCRζ/CD3 Complex, But Not CD28, Interact with Clathrin Adaptor Complexes AP-1 and AP-2". Journal of Immunology 163, № 4 (15 серпня 1999): 1868–79. http://dx.doi.org/10.4049/jimmunol.163.4.1868.

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Abstract The negative signaling receptor cytolytic T lymphocyte-associated Ag-4 (CTLA-4) resides primarily in intracellular compartments such as the Golgi apparatus of T cells. However, little is known regarding the molecular mechanisms that influence this accumulation. In this study, we demonstrate binding of the clathrin adaptor complex AP-1 with the GVYVKM motif of the cytoplasmic domain of CTLA-4. Binding occurred primarily in the Golgi compartment of T cells, unlike with AP-2 binding that occurs mostly with cell surface CTLA-4. Although evidence was not found to implicate AP-1 binding in the retention of CTLA-4 in the Golgi, AP-1 appears to play a role in shuttling of excess receptor from the Golgi to the lysosomal compartments for degradation. In support of this, increased CTLA-4 synthesis resulted in an increase in CTLA-4/AP-1 binding and a concomitant increase in the appearance of CTLA-4 in the lysosomal compartment. At the same time, the level of intracellular receptor was maintained at a constant level, suggesting that CTLA-4/AP-1 binding represents one mechanism to ensure steady state levels of intracellular CTLA-4 in T cells. Finally, we demonstrate that the TCRζ/CD3 complex (but not CD28) also binds to AP-1 and AP-2 complexes, thus providing a possible link between these two receptors in the regulation of T cell function.

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9

Mattera, Rafael, Sang Yoon Park, Raffaella De Pace, Carlos M. Guardia, and Juan S. Bonifacino. "AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation." Proceedings of the National Academy of Sciences 114, no. 50 (November 27, 2017): E10697—E10706. http://dx.doi.org/10.1073/pnas.1717327114.

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AP-4 is a member of the heterotetrameric adaptor protein (AP) complex family involved in protein sorting in the endomembrane system of eukaryotic cells. Interest in AP-4 has recently risen with the discovery that mutations in any of its four subunits cause a form of hereditary spastic paraplegia (HSP) with intellectual disability. The critical sorting events mediated by AP-4 and the pathogenesis of AP-4 deficiency, however, remain poorly understood. Here we report the identification of ATG9A, the only multispanning membrane component of the core autophagy machinery, as a specific AP-4 cargo. AP-4 promotes signal-mediated export of ATG9A from the trans-Golgi network to the peripheral cytoplasm, contributing to lipidation of the autophagy protein LC3B and maturation of preautophagosomal structures. These findings implicate AP-4 as a regulator of autophagy and altered autophagy as a possible defect in AP-4–deficient HSP.

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10

Szurmak, Blanka, Aleksandra Wysłouch-Cieszyńska, Małgorzata Wszelaka-Rylik, Wojciech Bal, and Marta Dobrzańska. "A diadenosine 5',5''-P1P4 tetraphosphate (Ap4A) hydrolase from Arabidopsis thaliana that is activated preferentially by Mn2+ ions." Acta Biochimica Polonica 55, no. 1 (March 13, 2008): 151–60. http://dx.doi.org/10.18388/abp.2008_3173.

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Asymmetrical diadenosine 5',5''-P(1)P(4) tetraphosphate (Ap(4)A) hydrolases are key enzymes controlling the in vivo concentration of Ap(4)A--an important signaling molecule involved in regulation of DNA replication and repair, signaling in stress response and apoptosis. Sequence homologies indicate that the genome of the model plant Arabidopsis thaliana contains at least three open reading frames encoding presumptive Ap(4)A hydrolases: At1g30110, At3g10620, and At5g06340. In this work we present efficient overexpression and detailed biochemical characteristics of the AtNUDX25 protein encoded by the At1g30110 gene. Aided by the determination of the binding constants of Mn(Ap(4)A) and Mg(Ap(4)A) complexes using isothermal titration calorimetry (ITC) we show that AtNUDX25 preferentially hydrolyzes Ap(4)A in the form of a Mn(2+) complex.

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11

Masaki, Shigeo, Kyoko Takeshima, Eiko Aoki та Atsuo Nakayama. "Binding specificity analysis between Neuroligin 4 and μ-Subunit of Adapter Protein Complex, AP-4". Neuroscience Research 68 (січень 2010): e144. http://dx.doi.org/10.1016/j.neures.2010.07.2212.

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12

Ishii, Noburo. "Trace of Frobenius endomorphism of an elliptic curve with complex multiplication." Bulletin of the Australian Mathematical Society 70, no. 1 (August 2004): 125–42. http://dx.doi.org/10.1017/s0004972700035875.

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Let E be an elliptic curve with complex multiplication by R, where R is an order of discriminant D < −4 of an imaginary quadratic field K. If a prime number p is decomposed completely in the ring class field associated with R, then E has good reduction at a prime ideal p of K dividing p and there exist positive integers u and υ such that 4p = u2 – Du;2. It is well known that the absolute value of the trace ap of the Frobenius endomorphism of the reduction of E modulo p is equal to u. We determine whether ap = u or ap = −u in the case where the class number of R is 2 or 3 and D is divisible by 3, 4 or 5.

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13

de Wilde, Jillian, Johanna De-Castro Arce, Peter J. F. Snijders, Chris J. L. M. Meijer, Frank Rösl, and Renske D. M. Steenbergen. "Alterations in AP-1 and AP-1 Regulatory Genes during HPV-Induced Carcinogenesis." Analytical Cellular Pathology 30, no. 1 (January 1, 2008): 77–87. http://dx.doi.org/10.1155/2008/279656.

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Background: Previous studies demonstrated a functional involvement of the AP-1 transcription factor in HPV-induced cervical carcinogenesis. Here, we aimed to obtain further insight in expression alterations of AP-1 family members during HPV-mediated transformation and their relationship to potential regulatory (Notch1, Net) and target (CADM1) genes.Methods: mRNA expression levels of c-Jun, JunB, junD, c-Fos, FosB, Fra-1, Fra-2, Notch1, Net and CADM1 were determined by quantitative RT-PCR in primary keratinocytes (n=5), early (n=4) and late (n=4) passages of non-tumorigenic HPV-immortalized keratinocytes and in tumorigenic cervical cancer cell lines (n=7). In a subset of cell lines protein expression and AP-1 complex composition was determined.Results: Starting in immortal stages c-Fos, Fra-2 and JunB expression became up regulated towards tumorigenicity, whereas Fra-1, c-Jun, Notch1, Net and CADM1 became down regulated. The onset of deregulated expression varied amongst the AP-1 members and was not directly related to altered Notch1, Net or CADM1 expression. Nevertheless, a shift in AP-1 complex composition from Fra-1/c-Jun to c-Fos/c-Jun heterodimers was only observed in tumorigenic cells.Conclusion: HPV-mediated transformation is associated with altered AP-1, Notch1, Net and CADM1 transcription. Whereas the onset of deregulated expression of various AP-1 family members became already manifest during the immortal state, a shift in AP-1 complex composition appeared a rather late event associated with tumorigenicity.

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14

Mattera, Rafael, Raffaella De Pace, and Juan S. Bonifacino. "The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia." Biochemical Society Transactions 48, no. 5 (October 21, 2020): 1877–88. http://dx.doi.org/10.1042/bst20190664.

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Heterotetrameric adaptor protein (AP) complexes play key roles in protein sorting and transport vesicle formation in the endomembrane system of eukaryotic cells. One of these complexes, AP-4, was identified over 20 years ago but, up until recently, its function remained unclear. AP-4 associates with the trans-Golgi network (TGN) through interaction with small GTPases of the ARF family and recognizes transmembrane proteins (i.e. cargos) having specific sorting signals in their cytosolic domains. Recent studies identified accessory proteins (tepsin, RUSC2 and the FHF complex) that co-operate with AP-4, and cargos (amyloid precursor protein, ATG9A and SERINC3/5) that are exported from the TGN in an AP-4-dependent manner. Defective export of ATG9A from the TGN in AP-4-deficient cells was shown to reduce ATG9A delivery to pre-autophagosomal structures, impairing autophagosome formation and/or maturation. In addition, mutations in AP-4-subunit genes were found to cause neurological dysfunction in mice and a form of complicated hereditary spastic paraplegia referred to as ‘AP-4-deficiency syndrome’ in humans. These findings demonstrated that mammalian AP-4 is required for the development and function of the central nervous system, possibly through its role in the sorting of ATG9A for the maintenance of autophagic homeostasis. In this article, we review the properties and functions of AP-4, and discuss how they might explain the clinical features of AP-4 deficiency.

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15

Paolini, Lucia, Annalisa Radeghieri, Sara Civini, Luigi Caimi, and Doris Ricotta. "The Epsilon Hinge-Ear Region Regulates Membrane Localization of the AP-4 Complex." Traffic 12, no. 11 (August 31, 2011): 1604–19. http://dx.doi.org/10.1111/j.1600-0854.2011.01262.x.

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16

Manowong, Machima, Eric Van Caemelbecke, M. Salomé Rodríguez-Morgade, John L. Bear, Karl M. Kadish, and Tomás Torres. "Synthesis and characterization of bis-[PcRu(CO)][Ru2(ap)4(C≡CC5H4N)2]." Journal of Porphyrins and Phthalocyanines 18, no. 01n02 (January 2014): 49–57. http://dx.doi.org/10.1142/s1088424613501228.

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A tetra-ruthenium complex containing two ruthenium(II) phthalocyanines and one metal–metal bonded diruthenium(III,III) unit was synthesized and investigated as to its electrochemical and spectroscopic properties in non-aqueous media. The title compound, represented as bis-[ PcRu ( CO )]-[ Ru 2( ap )4( C ≡ CC 5 H 4 N )2], where ap = 2-anilinopyridinate anion and Pc = the dianion of tetra-tert-butylphthalocyanine, was assembled by axial coordination of two PcRu ( CO ) macrocycles to pyridine groups of the complex which were themselves linked to the diruthenium(III,III) unit via alkyne groups. The tetra-ruthenium complex was characterized in solution and in the solid state by 1 H NMR, UV-visible and IR spectroscopies, mass spectrometry and cyclic voltammetry while thin-layer UV-visible spectroelectrochemistry was used to study the site of electron transfer. Eight redox processes occur in CH 2 Cl 2 or benzonitrile, four of which can be assigned to the macrocycles of PcRu ( CO ) and four to the central diruthenium unit of the molecule. The electrochemical and spectroscopic data suggest a weak electronic interaction between the diruthenium unit of [ Ru 2( ap )4( C ≡ CC 5 H 4 N )2] and the two externally linked Ru ( II ) phthalocyanines of the title compound.

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17

Romero, E., and R. Sullivan. "Complexity of the outward K+ current of the rat megakaryocyte." American Journal of Physiology-Cell Physiology 272, no. 5 (May 1, 1997): C1525—C1531. http://dx.doi.org/10.1152/ajpcell.1997.272.5.c1525.

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Megakaryocytes isolated from rat bone marrow express a voltage-dependent, outward K+ current with complex kinetics of activation and inactivation. We found that this current could be separated into at least two components based on differential responses to K+ channel blockers. One component, which exhibited features of the "transient" or "A-type" K+ current of excitable cells, was more strongly blocked by 4-aminopyridine (4-AP) than by tetrabutylammonium (TBA). This current, which we designated as "4-AP-sensitive" current, activated rapidly at potentials more positive than -40 mV and subsequently underwent rapid voltage-dependent inactivation. A separate current that activated slowly was blocked much more effectively by TBA than by 4-AP. This "TBA-sensitive" component, which resembled a typical delayed rectifier current, was much more resistant to voltage-dependent inactivation. The relative contribution of each of these components varied from cell to cell. The effect of charybdotoxin was similar to that of 4-AP. Our data indicate that the voltage-dependent K+ current of resting megakaryocytes is more complex than heretofore believed and support the emerging concept that megakaryocytes possess intricate electrophysiological properties.

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18

Traub, L. M., J. A. Ostrom, and S. Kornfeld. "Biochemical dissection of AP-1 recruitment onto Golgi membranes." Journal of Cell Biology 123, no. 3 (November 1, 1993): 561–73. http://dx.doi.org/10.1083/jcb.123.3.561.

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Recruitment of the Golgi-specific AP-1 adaptor complex onto Golgi membranes is thought to be a prerequisite for clathrin coat assembly on the TGN. We have used an in vitro assay to examine the translocation of cytosolic AP-1 onto purified Golgi membranes. Association of AP-1 with the membranes required GTP or GTP analogues and was inhibited by the fungal metabolite, brefeldin A. In the presence of GTP gamma S, binding of AP-1 to Golgi membranes was strictly dependent on the concentration of cytosol added to the assay. AP-1 recruitment was also found to be temperature dependent, and relatively rapid at 37 degrees C, following a lag period of 3 to 4 min. Using only an adaptor-enriched fraction from cytosol, purified myristoylated ARF1, and Golgi membranes, the GTP gamma S-dependent recruitment of AP-1 could be reconstituted. Our results show that the association of the AP-1 complex with Golgi membranes, like the coatomer complex, requires ARF, which accounts for the sensitivity of both to brefeldin A. In addition, they provide the basis for a model for the early biochemical events that lead to clathrin-coated vesicle formation on the TGN.

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19

Yuan, Pu-Qing, and Hong Yang. "Hypothyroidism increases Fos immunoreactivity in cholinergic neurons of brain medullary dorsal vagal complex in rats." American Journal of Physiology-Endocrinology and Metabolism 289, no. 5 (November 2005): E892—E899. http://dx.doi.org/10.1152/ajpendo.00108.2005.

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Hypo- or hyperthyroidism is associated with autonomic disorders. We studied Fos expression in the medullary dorsal motor nucleus of the vagus (DMV), nucleus tractus solitarii (NTS), and area postrema (AP) in four groups of rats with different thyroid states induced by a combination of drinking water and daily intraperitoneal injection for 1–4 wk: 1) tap water and vehicle; 2) 0.1% propylthiouracil (PTU) and vehicle; 3) PTU and thyroxine (T4; 2 μg/100 g); and 4) tap water and T4 (10 μg/100 g). The numbers of Fos immunoreactive (IR) positive neurons in the DMV, NTS, and AP were low in euthyroid rats but significantly higher in the 4-wk duration in hypothyroid rats, which were prevented by simultaneous T4 replacement. Hyperthyroidism had no effect on Fos expression in these areas. There were significant negative correlations between T4 levels and the numbers of Fos-IR-positive neurons in the DMV ( r = −0.6388, P < 0.008), NTS ( r = −0.6741, P < 0.003), and AP ( r = −0.5622, P < 0.004). Double staining showed that Fos immunoreactivity in the DMV of hypothyroid rats was mostly localized in choline acetyltransferase-containing neurons. Thyroid hormone receptors α1 and β2 were localized in the observed nuclei. These results indicate that thyroid hormone influences the DMV/NTS/AP neuronal activity, which may contribute to the vagal-related visceral disorders observed in hypothyroidism.

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20

Li, Qingjie, та Roderick H. Dashwood. "Activator Protein 2α Associates with Adenomatous Polyposis Coli/β-Catenin and Inhibits β-Catenin/T-cell Factor Transcriptional Activity in Colorectal Cancer Cells". Journal of Biological Chemistry 279, № 44 (24 серпня 2004): 45669–75. http://dx.doi.org/10.1074/jbc.m405025200.

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In most human colorectal cancers, mutations in the adenomatous polyposis coli gene (APC) orCTNNB1constitutively activate the β-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway. Here, we show that the transcription factor activator protein (AP)-2α inhibited a β-catenin/TCF-responsive reporter in human embryonic kidney 293 cells and in two human colorectal cancer lines, despite the fact that β-catenin and TCF-4 protein levels were unchanged in the nucleus. Co-immunoprecipitation studies revealed that AP-2α formed a complex with APC and β-catenin and that AP-2α disrupted β-catenin/TCF-4 interactions in the nucleus. Thus, AP-2α·APC·β-catenin complex formation appears to suppress β-catenin transactivation by shifting the pool of nuclear β-catenin toward an inactive form, having reduced binding to TCF/LEF transcription factors. GlutathioneS-transferase pull-down assays showed that AP-2α physically associated with APC rather than with β-catenin, and the AP-2α binding site was identified in the N terminus of APC, involving both the heptad and armadillo repeat domains, whereas the APC binding site in AP-2α was in the basic region of the C-terminal DNA binding domain. These findings provide the first evidence for a specific interaction between the tumor suppressor protein APC and the transcription factor AP-2α, and they suggest a link between the Wnt signaling pathway and various other pathways of development and differentiation associated with AP-2α.

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21

Larimore, Jennifer, Karine Tornieri, Pearl V. Ryder, Avanti Gokhale, Stephanie A. Zlatic, Branch Craige, Joshua D. Lee, et al. "The schizophrenia susceptibility factor dysbindin and its associated complex sort cargoes from cell bodies to the synapse." Molecular Biology of the Cell 22, no. 24 (December 15, 2011): 4854–67. http://dx.doi.org/10.1091/mbc.e11-07-0592.

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Dysbindin assembles into the biogenesis of lysosome-related organelles complex 1 (BLOC-1), which interacts with the adaptor protein complex 3 (AP-3), mediating a common endosome-trafficking route. Deficiencies in AP-3 and BLOC-1 affect synaptic vesicle composition. However, whether AP-3-BLOC-1–dependent sorting events that control synapse membrane protein content take place in cell bodies upstream of nerve terminals remains unknown. We tested this hypothesis by analyzing the targeting of phosphatidylinositol-4-kinase type II α (PI4KIIα), a membrane protein present in presynaptic and postsynaptic compartments. PI4KIIα copurified with BLOC-1 and AP-3 in neuronal cells. These interactions translated into a decreased PI4KIIα content in the dentate gyrus of dysbindin-null BLOC-1 deficiency and AP-3–null mice. Reduction of PI4KIIα in the dentate reflects a failure to traffic from the cell body. PI4KIIα was targeted to processes in wild-type primary cultured cortical neurons and PC12 cells but failed to reach neurites in cells lacking either AP-3 or BLOC-1. Similarly, disruption of an AP-3–sorting motif in PI4KIIα impaired its sorting into processes of PC12 and primary cultured cortical neuronal cells. Our findings indicate a novel vesicle transport mechanism requiring BLOC-1 and AP-3 complexes for cargo sorting from neuronal cell bodies to neurites and nerve terminals.

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22

LUNDMARK, Richard, та Sven R. CARLSSON. "The β-appendages of the four adaptor-protein (AP) complexes: structure and binding properties, and identification of sorting nexin 9 as an accessory protein to AP-2". Biochemical Journal 362, № 3 (8 березня 2002): 597–607. http://dx.doi.org/10.1042/bj3620597.

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Adaptor protein (AP) complexes are essential components for the formation of coated vesicles and the recognition of cargo proteins for intracellular transport. Each AP complex exposes two appendage domains with that function to bind regulatory accessory proteins in the cytosol. Secondary structure predictions, sequence alignments and CD spectroscopy were used to relate the β-appendages of all human AP complexes to the previously published crystal structure of AP-2. The results suggested that the β-appendages of AP-1, AP-2 and AP-3 have similar structures, consisting of two subdomains, whereas that of AP-4 lacks the inner subdomain. Pull-down and overlay assays showed partial overlap in the binding specificities of the β-appendages of AP-1 and AP-2, whereas the corresponding domain of AP-3 displayed a unique binding pattern. That AP-4 may have a truncated, non-functional domain was indicated by its apparent inability to bind any proteins from cytosol. Of several novel β-appendage-binding proteins detected, one that had affinity exclusively for AP-2 was identified as sorting nexin 9 (SNX9). SNX9, which contains a phox and an Src homology 3 domain, was found in large complexes and was at least partially associated with AP-2 in the cytosol. SNX9 may function to assist AP-2 in its role at the plasma membrane.

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Burgos, Patricia V., Gonzalo A. Mardones, Adriana L. Rojas, Luis L. P. daSilva, Yogikala Prabhu, James H. Hurley, and Juan S. Bonifacino. "Sorting of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex." Developmental Cell 18, no. 3 (March 2010): 425–36. http://dx.doi.org/10.1016/j.devcel.2010.01.015.

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Aguilar, Ruben C., Markus Boehm, Inna Gorshkova, Robert J. Crouch, Kazuhiro Tomita, Takashi Saito, Hiroshi Ohno та Juan S. Bonifacino. "Signal-binding Specificity of the μ4 Subunit of the Adaptor Protein Complex AP-4". Journal of Biological Chemistry 276, № 16 (3 січня 2001): 13145–52. http://dx.doi.org/10.1074/jbc.m010591200.

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Fields, Ian C., Elina Shteyn, Marc Pypaert, Véronique Proux-Gillardeaux, Richard S. Kang, Thierry Galli, and Heike Fölsch. "v-SNARE cellubrevin is required for basolateral sorting of AP-1B–dependent cargo in polarized epithelial cells." Journal of Cell Biology 177, no. 3 (May 7, 2007): 477–88. http://dx.doi.org/10.1083/jcb.200610047.

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The epithelial cell–specific adaptor complex AP-1B is crucial for correct delivery of many transmembrane proteins from recycling endosomes to the basolateral plasma membrane. Subsequently, membrane fusion is dependent on the formation of complexes between SNARE proteins located at the target membrane and on transport vesicles. Although the t-SNARE syntaxin 4 has been localized to the basolateral membrane, the v-SNARE operative in the AP-1B pathway remained unknown. We show that the ubiquitously expressed v-SNARE cellubrevin localizes to the basolateral membrane and to recycling endosomes, where it colocalizes with AP-1B. Furthermore, we demonstrate that cellubrevin coimmunoprecipitates preferentially with syntaxin 4, implicating this v-SNARE in basolateral fusion events. Cleavage of cellubrevin with tetanus neurotoxin (TeNT) results in scattering of AP-1B localization and missorting of AP-1B–dependent cargos, such as transferrin receptor and a truncated low-density lipoprotein receptor, LDLR-CT27. These data suggest that cellubrevin and AP-1B cooperate in basolateral membrane trafficking.

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Craige, Branch, Gloria Salazar, and Victor Faundez. "Phosphatidylinositol-4-Kinase Type II Alpha Contains an AP-3–sorting Motif and a Kinase Domain That Are Both Required for Endosome Traffic." Molecular Biology of the Cell 19, no. 4 (April 2008): 1415–26. http://dx.doi.org/10.1091/mbc.e07-12-1239.

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The adaptor complex 3 (AP-3) targets membrane proteins from endosomes to lysosomes, lysosome-related organelles and synaptic vesicles. Phosphatidylinositol-4-kinase type II α (PI4KIIα) is one of several proteins possessing catalytic domains that regulate AP-3–dependent sorting. Here we present evidence that PI4KIIα uniquely behaves both as a membrane protein cargo as well as an enzymatic regulator of adaptor function. In fact, AP-3 and PI4KIIα form a complex that requires a dileucine-sorting motif present in PI4KIIα. Mutagenesis of either the PI4KIIα-sorting motif or its kinase-active site indicates that both are necessary to interact with AP-3 and properly localize PI4KIIα to LAMP-1–positive endosomes. Similarly, both the kinase activity and the sorting signal present in PI4KIIα are necessary to rescue endosomal PI4KIIα siRNA-induced mutant phenotypes. We propose a mechanism whereby adaptors use canonical sorting motifs to selectively recruit a regulatory enzymatic activity to restricted membrane domains.

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Zhu, Yunxiang, Linton M. Traub, and Stuart Kornfeld. "ADP-Ribosylation Factor 1 Transiently Activates High-Affinity Adaptor Protein Complex AP-1 Binding Sites On Golgi Membranes." Molecular Biology of the Cell 9, no. 6 (June 1998): 1323–37. http://dx.doi.org/10.1091/mbc.9.6.1323.

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Association of the Golgi-specific adaptor protein complex 1 (AP-1) with the membrane is a prerequisite for clathrin coat assembly on the trans-Golgi network (TGN). The AP-1 adaptor is efficiently recruited from cytosol onto the TGN by myristoylated ADP-ribosylation factor 1 (ARF1) in the presence of the poorly hydrolyzable GTP analog guanosine 5′-O-(3-thiotriphosphate) (GTPγS). Substituting GTP for GTPγS, however, results in only poor AP-1 binding. Here we show that both AP-1 and clathrin can be recruited efficiently onto the TGN in the presence of GTP when cytosol is supplemented with ARF1. Optimal recruitment occurs at 4 μM ARF1 and with 1 mM GTP. The AP-1 recruited by ARF1·GTP is released from the Golgi membrane by treatment with 1 M Tris-HCl (pH 7) or upon reincubation at 37°C, whereas AP-1 recruited with GTPγS or by a constitutively active point mutant, ARF1(Q71L), remains membrane bound after either treatment. An incubation performed with added ARF1, GTP, and AlFn, used to block ARF GTPase-activating protein activity, results in membrane-associated AP-1, which is largely insensitive to Tris extraction. Thus, ARF1·GTP hydrolysis results in lower-affinity binding of AP-1 to the TGN. Using two-stage assays in which ARF1·GTP first primes the Golgi membrane at 37°C, followed by AP-1 binding on ice, we find that the high-affinity nucleating sites generated in the priming stage are rapidly lost. In addition, the AP-1 bound to primed Golgi membranes during a second-stage incubation on ice is fully sensitive to Tris extraction, indicating that the priming stage has passed the ARF1·GTP hydrolysis point. Thus, hydrolysis of ARF1·GTP at the priming sites can occur even before AP-1 binding. Our finding that purified clathrin-coated vesicles contain little ARF1 supports the concept that ARF1 functions in the coat assembly process rather than during the vesicle-uncoating step. We conclude that ARF1 is a limiting factor in the GTP-stimulated recruitment of AP-1 in vitro and that it appears to function in a stoichiometric manner to generate high-affinity AP-1 binding sites that have a relatively short half-life.

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Niebler, Stephan, Peter Angele, Richard Kujat, and Anja K. Bosserhoff. "Hypoxia-Inducible Factor 1 Is an Inductor of Transcription Factor Activating Protein 2 Epsilon Expression during Chondrogenic Differentiation." BioMed Research International 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/380590.

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The transcription factor AP-2ε(activating enhancer-binding protein epsilon) is expressed in cartilage of humans and mice. However, knowledge about regulatory mechanisms influencing AP-2εexpression is limited. Using quantitative real time PCR, we detected a significant increase in AP-2εmRNA expression comparing initial and late stages of chondrogenic differentiation processesin vitroandin vivo. Interestingly, in these samples the expression pattern of the prominent hypoxia marker geneangiopoietin-like 4 (Angptl4)strongly correlated with that ofAP-2εsuggesting that hypoxia might represent an external regulator of AP-2εexpression in mammals. In order to show this, experiments directly targeting the activity of hypoxia-inducible factor-1 (HIF1), the complex mediating responses to oxygen deprivation, were performed. While the HIF1-activating compounds 2,2′-dipyridyl and desferrioxamine resulted in significantly enhanced mRNA concentration of AP-2ε, siRNA against HIF1αled to a significantly reduced expression rate ofAP-2ε. Additionally, we detected a significant upregulation of the AP-2εmRNA level after oxygen deprivation. In sum, these different experimental approaches revealed a novel role for the HIF1 complex in the regulation of theAP-2εgene in cartilaginous cells and underlined the important role of hypoxia as an important external regulatory stimulus during chondrogenic differentiation modulating the expression of downstream transcription factors.

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Xia, Longfei, Lichao Hu, Hongxiang Xie, Ting Wang, Ya Xu, Jingjing Liu, Xiaolei Zhang, Jinchuan Yan та Hong Zhou. "Both NF-κB and c-Jun/AP-1 involved in anti-β2GPI/β2GPI-induced tissue factor expression in monocytes". Thrombosis and Haemostasis 109, № 04 (2013): 643–51. http://dx.doi.org/10.1160/th12-09-0655.

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SummaryOur previous data has demonstrated that Toll-like receptor 4 (TLR4) and its signalling pathway can contribute to anti-β2-glycoprotein I/β2-glycoprotein I (anti-β2GPI/β2GPI) -induced tissue factor (TF) expression in human blood monocytes and acute monocytic leukaemia cell line THP-1. However, its downstream nuclear transcription factors have not been well explored. In the current study, we further investigated whether nuclear factor kappa B (NF-κB) and activator protein (AP-1) were activated and their roles in anti-β2GPI/β2GPI complex stimulating TF expression. The results showed that treatment of the cells with anti-β2GPI (10 µg/ml)/β2GPI (100 mg/ml) complex could markedly increase the levels of phosphorylated NF-κB (p-NF-κB p65) and c-Jun/AP-1 (p-c-Jun), as well as TF expression. Both NF-κB inhibitor PDTC (20 µM) and AP-1 inhibitor curcumin (25 mM) could attenuate TF expression induced by anti-β2GPI/β2GPI or APS-IgG/β2GPI complex. Combination of any two inhibitors of MAPKs (SB203580/U0126 or SB203580/SP600125 or U0126/SP600125) could decrease activation of NF-κB. SB203580/SP600125 or U0126/SP600125, but not SB203580/U0126, could reduce the phosphorylation of c-Jun/AP-1. Neither NF-κB nor c-Jun/AP-1 activation caused by anti-β2GPI/β2GPI complex could be affected by TLR4 inhibitor TAK-242. In conclusion, our results indicate that both NF-κB and c-Jun/AP-1 can be activated and play important roles in the process of anti-β2GPI/β2GPI-induced TF expression in monocytes, thereby contributing to the pathological processes of antiphospholipid syndrome.

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Schwarz, Neil A., John E. Kovaleski, Robert J. Heitman, Larry R. Gurchiek, and Coral Gubler-Hanna. "Arthrometric Measurement of Ankle-Complex Motion: Normative Values." Journal of Athletic Training 46, no. 2 (March 1, 2011): 126–32. http://dx.doi.org/10.4085/1062-6050-46.2.126.

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Abstract Context: Valid and reliable measurements of ankle-complex motion have been reported using the Hollis Ankle Arthrometer. No published normative data of ankle-complex motion obtained from ankle arthrometry are available for use as a reference for clinical decision making. Objective: To describe the distribution variables of ankle-complex motion in uninjured ankles and to establish normative reference values for use in research and to assist in clinical decision making. Design: Descriptive laboratory study. Setting: University research laboratory. Patients or Other Participants: Both ankles of 50 men and 50 women (age = 21.78 ± 2.0 years [range, 19–25 years]) were tested. Intervention(s): Each ankle underwent anteroposterior (AP) and inversion-eversion (I-E) loading using an ankle arthrometer. Main Outcome Measure(s): Recorded anterior, posterior, and total AP displacement (millimeters) at 125 N and inversion, eversion, and total I-E rotation (degrees) at 4 Nm. Results: Women had greater ankle-complex motion for all variables except for posterior displacement. Total AP displacement of the ankle complex was 18.79 ± 4.1 mm for women and 16.70 ± 4.8 mm for men (U = 3742.5, P < .01). Total I-E rotation of the ankle complex was 42.10° ± 9.0° for women and 34.13° ± 10.1° for men (U = 2807, P < .001). All variables were normally distributed except for anterior displacement, inversion rotation, eversion rotation, and total I-E rotation in the women's ankles and eversion rotation in the men's ankles; these variables were skewed positively. Conclusions: Our study increases the available database on ankle-complex motion, and it forms the basis of norm-referenced clinical comparisons and the basis on which quantitative definitions of ankle pathologic conditions can be developed.

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Lo, William B., Kyaw Z. Thant, Jameel Kaderbhai, Nicholas White, Hiroshi Nishikawa, Michael Stephen Dover, Martin Evans, and Desiderio Rodrigues. "Posterior calvarial distraction for complex craniosynostosis and cerebellar tonsillar herniation." Journal of Neurosurgery: Pediatrics 26, no. 4 (October 2020): 421–30. http://dx.doi.org/10.3171/2020.4.peds19742.

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OBJECTIVEChildren with syndromic, multisuture, and lambdoid craniosynostosis undergoing calvarial surgery often have Chiari malformation type I (CM-I) (or cerebellar tonsillar herniation). The optimal management of this patient group, including the surgical techniques and timing of surgery, remains uncertain. Posterior calvarial distraction (PCD) is an effective method to increase the supratentorial cranial volume and improve raised intracranial pressure in children with complex craniosynostosis. This study investigated the efficacy of PCD in posterior fossa (PF) volume expansion and treatment of CM-I and associated syringomyelia (syrinx) in this group of children.METHODSThis retrospective study included patients who were surgically treated between 2006 and 2015. Over 10 years, 16 patients with multisuture synostosis, lambdoid synostosis, or craniosynostosis associated with a confirmed genetic syndrome, and a concurrent CM-I, were included. The mean age at the time of surgery was 5.1 years (range 8 months–18 years). Fourteen patients had pansynostosis and 2 had lambdoid synostosis. Eight had a confirmed syndromic diagnosis (Crouzon in 8, Apert in 4, Pfeiffer in 1, and Saethre-Chotzen in 1). Ten patients had raised intracranial pressure; 4 had syringomyelia.RESULTSThe average clinical follow-up was 50 months (range 9–116 months). Clinically, 9 patients improved, 7 remained stable, and none deteriorated. The average distraction distance was 23 mm (range 16–28 mm). The PF anterior-posterior (AP) distance/width ratio increased from 0.73 to 0.80 mm (p = 0.0004). Although an osteotomy extending inferior to the torcula (compared with superior) was associated with a larger absolute PF AP distance increase (13 vs 6 mm, p = 0.028), such a difference was not demonstrable when the PF AP distance/width ratio was calculated. Overall, the mean tonsillar herniation improved from 9.3 to 6.0 mm (p = 0.011). Syrinx dimensions also improved in the AP (from 7.9 to 3.1 mm) and superior-inferior (from 203 to 136 mm) dimensions. No patients required further foramen magnum decompression for CM. Of the 16 patients, 2 had subsequent frontoorbital advancement and remodeling, of which 1 was for volume expansion and 1 was for cosmetic purposes. Two patients required CSF shunt insertion after PCD.CONCLUSIONSFollowing PCD, PF volume increased as well as supratentorial volume. This morphometric change was observed in osteotomies both inferior and superior to the torcula. The PF volume increase resulted in improvement of cerebellar tonsillar herniation and syrinx. PCD is an efficacious first-line, single-stage treatment for concurrent pansynostosis and lambdoid craniosynostosis, CM-I, and syrinx.

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Chedid, M., B. K. Yoza, J. W. Brooks, and S. B. Mizel. "Activation of AP-1 by IL-1 and phorbol esters in T cells. Role of protein kinase A and protein phosphatases." Journal of Immunology 147, no. 3 (August 1, 1991): 867–73. http://dx.doi.org/10.4049/jimmunol.147.3.867.

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Abstract We have examined the regulation of the AP-1 transcription complex in the IL-1-responsive murine T cell thymoma cell line EL-4 6.1 C10. Our results demonstrate that AP-1-mediated gene expression in T cells may be regulated by several signaling pathways and factors, including IL-1, protein kinase C, protein kinase A (PKA), and one or more serine/threonine-specific protein phosphatases. The activation of protein kinase C results in an increase in nuclear AP-1 DNA binding activity, as well as enhanced gene expression. IL-1 and agents that elevate intracellular cAMP levels do not, by themselves, induce AP-1 activation, but they synergize with phorbol esters. IL-1 and forskolin may enhance AP-1 function by different mechanisms, because forskolin enhanced gene expression without producing an increase in nuclear AP-1 DNA binding, whereas IL-1 increased AP-1-binding activity and gene expression. These observations, in conjunction with the lack of a demonstrable effect of IL-1 on cAMP production in EL-4 cells, are consistent with the view that IL-1 enhances AP-1 activation by a pathway that does not directly involve cAMP and PKA. However, the induction of AP-1 activity by IL-1 and phorbol esters is dependent upon the presence of PKA, as evidenced by the loss of AP-1 inducibility in cells transfected with a cDNA encoding protein kinase inhibitor, a specific inhibitor of PKA. The effect of protein kinase inhibitor on AP-1 activation in response to IL-1 and tetradecanoyl-phorbol-13-acetate was reversed in the presence of the serine/threonine protein phosphatase inhibitor okadaic acid. Thus, the level of AP-1 activity in T cells may be determined by the balance between the activities of several serine/threonine protein kinases and phosphatases.

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Boehm, M. "Functional and physical interactions of the adaptor protein complex AP-4 with ADP-ribosylation factors (ARFs)." EMBO Journal 20, no. 22 (November 15, 2001): 6265–76. http://dx.doi.org/10.1093/emboj/20.22.6265.

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Bear, J. L., L. M. Liu, and K. M. Kadish. "Structural, ESR, and electrochemical properties of two [Rh2(ap)4]+ geometric isomers (ap = 2-anilinopyridinate). A true mixed-valent rhodium(II)-rhodium(III) complex." Inorganic Chemistry 26, no. 18 (September 1987): 2927–29. http://dx.doi.org/10.1021/ic00265a002.

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Moreno-De-Luca, A., S. L. Helmers, H. Mao, T. G. Burns, A. M. A. Melton, K. R. Schmidt, P. M. Fernhoff, D. H. Ledbetter, and C. L. Martin. "Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability." Journal of Medical Genetics 48, no. 2 (October 23, 2010): 141–44. http://dx.doi.org/10.1136/jmg.2010.082263.

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Yap, C. "Adaptor protein complex-4 (AP-4) is expressed in the central nervous system neurons and interacts with glutamate receptor δ2". Molecular and Cellular Neuroscience 24, № 2 (жовтень 2003): 283–95. http://dx.doi.org/10.1016/s1044-7431(03)00164-7.

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Kuliev, Kerim Avaz oglu, Shafa Aga qizi Mamedova, and Naiba Nasraddin qizi Efendiyeva. "Investigation of nikel(II) complexing with 2,6-dimerkapto-4-methilphenol and aminophenols." Izvestiya of Saratov University. New Series. Series: Chemistry. Biology. Ecology 21, no. 1 (2021): 31–43. http://dx.doi.org/10.18500/1816-9775-2021-21-1-31-43.

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Complexing of nickel(II) with 2,6-dimercapto-4-methylphenol (DMMP) and hydrophobic amines was studied using physicochemical methods. Hydroxyl-containing amines-aminophenols (AP) were used as a hydrophobic amine. On the part of aminophenols, 2 (N, N-dimethylaminomethyl)-4-methylphenol (AP1), 2 (N, N-dimethylaminomethyl)-4-chlorophenol (AP2), and 2 (N, N-dimethylaminomethyl)-4-bromophenol (AP3) were used. Mixed-ligand complexes were formed in a weakly acidic medium (pHopt 4.6–6.4). Ni(II) is recovered by chloroform by 98.6–99.5% in the form of a mixed-ligand complex (MLC) per single extraction. The optimal conditions for the formation and extraction of these compounds are 1.12 × 10-3 mol/L concentration of DMMP and 0.88 × 10-3 mol/L – AP. Changing the concentration of the reagents does not change the composition of the complexes. MLC of Ni(II) with DMMP and AP are stable in aqueous and organic solvents and do not decompose within three days and for more than a month after extraction. The ratio of reacting components in MLC corresponds to Ni (II): DMMP : AP = 1 : 2 : 2. in the formation of MLC, the coordinating ion is Ni2+. Complexing proceeds with the displacement of a proton from a DMMP molecule. Maximum light absorption is observed at λ = 520–530 nm. The molar coefficients of light absorption are (3.78-3.95) × 10 4. Based on the obtained data photometric methods for the determination of nickel in various industrial and natural objects were developed.

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Bondarenko, Vladimir E., and Randall L. Rasmusson. "Transmural heterogeneity of repolarization and Ca2+ handling in a model of mouse ventricular tissue." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 2 (August 2010): H454—H469. http://dx.doi.org/10.1152/ajpheart.00907.2009.

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Mouse hearts have a diversity of action potentials (APs) generated by the cardiac myocytes from different regions. Recent evidence shows that cells from the epicardial and endocardial regions of the mouse ventricle have a diversity in Ca2+ handling properties as well as K+ current expression. To examine the mechanisms of AP generation, propagation, and stability in transmurally heterogeneous tissue, we developed a comprehensive model of the mouse cardiac cells from the epicardial and endocardial regions of the heart. Our computer model simulates the following differences between epicardial and endocardial myocytes: 1) AP duration is longer in endocardial and shorter in epicardial myocytes, 2) diastolic and systolic intracellular Ca2+ concentration and intracellular Ca2+ concentration transients are higher in paced endocardial and lower in epicardial myocytes, 3) Ca2+ release rate is about two times larger in endocardial than in epicardial myocytes, and 4) Na+/Ca2+ exchanger rate is greater in epicardial than in endocardial myocytes. Isolated epicardial cells showed a higher threshold for stability of AP generation but more complex patterns of AP duration at fast pacing rates. AP propagation velocities in the model of two-dimensional tissue are close to those measured experimentally. Simulations show that heterogeneity of repolarization and Ca2+ handling are sustained across the mouse ventricular wall. Stability analysis of AP propagation in the two-dimensional model showed the generation of Ca2+ alternans and more complex transmurally heterogeneous irregular structures of repolarization and intracellular Ca2+ transients at fast pacing rates.

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Zhang, Ximbo, and Frederick L. Kiechle. "Cytosine Arabinoside Substitution Decreases Transcription Factor–DNA Binding Element Complex Formation." Archives of Pathology & Laboratory Medicine 128, no. 12 (December 1, 2004): 1364–71. http://dx.doi.org/10.5858/2004-128-1364-casdtf.

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Abstract Context.—The pyrimidine nucleoside analog, cytosine arabinoside (Ara-C), is an effective therapeutic agent for acute leukemia. The phosphorylated triphosphate, cytosine arabinoside triphosphate, competes with deoxycytosine triphosphate as a substrate for incorporation into DNA. Once incorporated into DNA, it inhibits DNA polymerase and topoisomerase I and modifies the tertiary structure of DNA. Objective.—To determine if the substitution of Ara-C for cytosine in double-stranded oligonucleotides that contain 4 specific transcription factor binding sites (TATA, GATA, C/EBP, and AP-2α) alters transcription factor binding to their respective DNA binding elements. Design.—Transcription factors were obtained from nuclear extracts from human promyelocytic leukemia HL-60 cells. [32P]-end-labeled double-stranded oligonucleotides that contained 1 or 2 specific transcription factor binding sites with or without Ara-C substitution for cytosine were used to assess transcription factor binding by electrophoretic mobility shift assay. Results.—The substitution of Ara-C for cytosine within and outside the transcription factor binding element (AP-2α, C/EBP), outside the binding element only (GATA, TATA), or within the binding element only (AP-2α) all result in a reduction in transcription factor binding to their respective DNA binding element. Conclusion.—The reduction of the binding capacity of transcription factors with their respective DNA binding elements may depend on structural changes within oligonucleotides induced by Ara-C incorporation. This altered binding capacity of transcription factors to their DNA binding elements may represent one mechanism for Ara-C cytotoxicity secondary to inhibition of transcription of new messenger RNAs and, subsequently, translation of new proteins.

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Frommer, Lara, and George J. Kahaly. "Autoimmune Polyendocrinopathy." Journal of Clinical Endocrinology & Metabolism 104, no. 10 (April 26, 2019): 4769–82. http://dx.doi.org/10.1210/jc.2019-00602.

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Abstract Context This mini-review offers an update on the rare autoimmune polyendocrinopathy (AP) syndrome with a synopsis of recent developments. Design and Results Systematic search for studies related to pathogenesis, immunogenetics, screening, diagnosis, clinical spectrum, and epidemiology of AP. AP (orphan code ORPHA 282196) is defined as the autoimmune-induced failure of at least two glands. AP is divided into the rare juvenile type I and the adult types II to IV. The prevalence is 1:100,000 and 1:20,000 for types I and types II to IV, respectively. Whereas type I (ORPHA 3453) is a monogenetic syndrome with an autosomal recessive transmission related to mutations in the autoimmune regulator (AIRE) gene, types II to IV are genetically complex multifactorial syndromes that are strongly associated with certain alleles of HLA genes within the major histocompatibility complex located on chromosome 6, as well as the cytotoxic T lymphocyte antigen 4 and the protein tyrosine phosphatase nonreceptor type 22 genes. Addison disease is the major endocrine component of type II (ORPHA 3143), whereas the coexistence of type 1 diabetes and autoimmune thyroid disease is characteristic for type III (ORPHA 227982). Genetic screening for the AIRE gene is useful in patients with suspected type I, whereas serological screening (i.e., diabetes/adrenal antibodies) is required in patients with monoglandular autoimmunity and suspected AP. If positive, functional endocrine testing of the antibody-positive patients as well as serological screening of their first-degree relatives is recommended. Conclusion Timely diagnosis, genetic counseling, and optimal long-term management of AP is best offered in specialized centers.

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Kon, Noriyoshi, Nobuhiko Iki, Takashi Kajiwara, Tasuku Ito, and Sotaro Miyano. "Ap-tert-Butyldithiacalix[4]arene-Copper(II) Complex Having Double-cone Shape of Unique Heteroditopic Inclusion Behavior." Chemistry Letters 33, no. 8 (August 2004): 1046–47. http://dx.doi.org/10.1246/cl.2004.1046.

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Ceddia, M. A., and J. A. Woods. "Exercise suppresses macrophage antigen presentation." Journal of Applied Physiology 87, no. 6 (December 1, 1999): 2253–58. http://dx.doi.org/10.1152/jappl.1999.87.6.2253.

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This study determined the effects of exercise on the ability of macrophages (Mφ) to present antigen to T cells. Pathogen-free male Balb/c mice (8 ± 2 wk of age) were randomly assigned to either home cage control, moderate exercise (Mod; 18 m/min, 5% grade, 0.5 h/day), exhaustive exercise (Exh, 18–30 m/min, 3 h/day), or treadmill control groups. The mice underwent treatments for 4 days during peritoneal thioglycolate inflammation. Peritoneal Mφ were harvested, purified, and incubated with chicken ovalbumin (C-OVA; 0–10 mg/ml) for 18 h. Mφ were then cocultured with C-OVA-specific T cells for 48 h, and the supernatants were analyzed via ELISA for interleukin-2 as an indication of Mφ antigen presentation (AP). Exh exhibited suppressed (∼25–34%) Mφ AP across a wide range of C-OVA doses when measured immediately, 3, and 24 h postexercise. In contrast, Mod had reduced Mφ AP only at 3 h postexercise. Mφ AP was also lower in the treadmill control (4–27%) compared with the home cage control group, but was significantly higher than Exh. The reduction in Mφ AP was not due to exercise-induced differences in Mφ number, percentage, or expression of intercellular adhesion molecule-1, B7–2, or major histocompatability complex II, molecules important in AP. In conclusion, our data lend evidence that may help explain the increased incidence of infection observed after prolonged exhaustive exercise or overtraining.

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Galdiero, Massimiliano, Mariateresa Vitiello, Emma Sanzari, Marina D’Isanto, Annalisa Tortora, Anna Longanella та Stefania Galdiero. "Porins from Salmonella enterica Serovar Typhimurium Activate the Transcription Factors Activating Protein 1 and NF-κB through the Raf-1-Mitogen-Activated Protein Kinase Cascade". Infection and Immunity 70, № 2 (лютий 2002): 558–68. http://dx.doi.org/10.1128/iai.70.2.558-568.2002.

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ABSTRACT In this study we examined the ability of Salmonella enterica serovar Typhimurium porins to activate activating protein 1 (AP-1) and nuclear factor κB (NF-κB) through the mitogen-activated protein kinase (MAPK) cascade, and we identified the AP-1-induced protein subunits. Our results demonstrate that these enzymes may participate in cell signaling pathways leading to AP-1 and NF-κB activation following porin stimulation of cells. Raf-1 was phosphorylated in response to the treatment of U937 cells with porins; moreover, the porin-mediated increase in Raf-1 phosphorylation is accompanied by the phosphorylation of MAPK kinase 1/2 (MEK1/2), p38, extracellular-signal-regulated kinase 1/2, and c-Jun N-terminal kinase. We used three different inhibitors of phosphorylation pathways: 2′-amino-3′-methoxyflavone (PD-098059), a selective inhibitor of MEK1 activator and the MAPK cascade; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a specific inhibitor of the p38 pathway; and 7β-acetoxy-1α,6β,9α-trihydroxy-8,13-epoxy-labd-14-en-11-one (forskolin), an inhibitor at the level of Raf-1 kinase. PD-098059 pretreatment of cells decreases AP-1 and NF-κB activation by lipopolysaccharide (LPS) but not by porins, and SB203580 pretreatment of cells decreases mainly AP-1 and NF-κB activation by porins; in contrast, forskolin pretreatment of cells does not affect AP-1 and NF-κB activation following either porin or LPS stimulation. Our data suggest that the p38 signaling pathway mainly regulates AP-1 and NF-κB activation in cells treated with S. enterica serovar Typhimurium porins. Antibody electrophoretic mobility shift assays showed that JunD and c-Fos binding is found in cells treated with porins, in cells treated with LPS, and in unstimulated cells. However, by 30 to 60 min of stimulation, a different complex including c-Jun appears in cells treated with porins or LPS, while the Fra-2 subunit is present only after porin stimulation. These data suggest different molecular mechanisms of activation induced by porins or by LPS.

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44

Tserkovniuk, Ruslan, Roman Yanchij, Oleksandr Plyska, Marta Kovbasnyuk, Ivanna Chendey, Magdalena Hagner-Derengowska, Xawery Zukow, Krystian Kałużny, Radosław Muszkieta та Walery Zukow. "Relationships between geomagnetic Ар-indeх and parameters of the immunity in patients with neuroendocrine-immune complex dysfunction in former sportsmen". Journal of Education, Health and Sport 11, № 7 (31 липня 2021): 335–48. http://dx.doi.org/10.12775/jehs.2021.11.07.034.

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Background. The effect of geomagnetism on human immunity has so far been studied through long-term observations. Recently, we have been detected the immediate immunotropic effects of the disturbances of the geomagnetic field (Ap-index) at multiple sclerosis patients. The aim of this study was to identify the immunotropic effects of geomagnetism on another contingent of people. Material and methods. The object of observation were 21 men (24-63 y) and 20 women (33-62 y) with neuroendocrine-immune complex dysfunction. Each patient was tested twice with an interval of 4 days. Observations were carried out on 09.06. and 13.06. 2015, 14.09 and 18.09. 2015, 27-28.03. and 04-05.04. 2018, 28.01. and 01.02. 2019. Retrospectively we recorded the geomagnetic Ap-Index on the day of testing and during the previous 7 days, using resource https://www.spaceweatherlive.com/. The content of subpopulations of lymphocytes expressing CD3, CD4, CD25, CD8, CD22 and CD56 receptors as well as the serum concentration of circulating immune complexes, immunoglobulins classes M, G, A, C-reactive protein and IL-1β was determined. The state of phagocytic function of neutrophils estimated by microbial count and phagocytic and killing indices against Staphylococcus aureus and Escherichia coli. Results. During the week, the average level of Ap-index ranged from 7 to 13 nT. Maximum coefficients of multiple correlation with immunity parameters were detected for Ap-index on the eve of blood sampling (R=0,768) and 5 days before it (R=0,758) while the minimum on 3 (R=0,541) and 2 (R=0,479) days before sampling. The canonical correlation between Ap-indices for 7 days before and on the day of testing, on the one hand, and the immunity parameters - on the other hand, was very strong: R=0,921; R2=0,849; χ2(200)=375; p<10-6. Conclusion. Disturbances of the geomagnetic field (Ap-index) has a significant immediate modulating effect on the immune parameters, mostly phagocytosis completeness, Igg A and M serum concentration, T-helper and B lymphocytes as well as eosinophils, rod-shaped neutrophils and monocytes blood level.

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Tserkovniuk, Ruslan, Anatoliy Gozhenko, Tetyana Korolyshyn, Sofiya Ruzhylo, Volodymyr Kikhtan, Vitalij Fil, Anatoliy Anchev, Walery Zukow, Roman Yanchij та Igor Popovych. "Relationships between geomagnetic Ар-indeх and HRV and endocrine parameters in patients with dysfunction of the neuroendocrine-immune complex". Journal of Education, Health and Sport 11, № 11 (30 листопада 2021): 295–303. http://dx.doi.org/10.12775/jehs.2021.11.11.029.

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Background. Recently, on the example of two cohort of patients, we found that disturbances of the geomagnetic field cause a significant immediate modulating effect on the level of immune parameters in the blood. The data available in the literature give grounds for assumptions about the direct effect of disturbances of the geomagnetic field on immunocytes, and indirectly, through immunotropic neurotransmitters and hormones. Our hypothesis is as follows. Disturbances of the geomagnetic field are perceived by acupuncture points. The information obtained is transmitted to neurons and endocrinocytes, the mediators of which, in turn, affect immunocytes. The purpose of this study is to test this hypothesis. Material and methods. The object of observation were 21 men (24-63 y) and 20 women (30-72 y) with neuroendocrine-immune complex dysfunction. Each patient was tested twice with an interval of 4 days. Retrospectively we recorded the geomagnetic Ap-Index on the day of testing and during the previous 7 days, using resource https://www.spaceweatherlive.com/. Recorded the heart rate variability (HRV) parameters, determined the plasma level of cortisol, triiodothyronine and testosterone. Results. During the week, the average level of Ap-index ranged from 7 to 13 nT. Maximum coefficients of multiple correlation with HRV&Hormonal parameters were detected for Ap-index on 2 (R=0,506) and 7 (R=0,403) days before testing. The canonical correlation between Ap-indices for 7 days before and on the day of testing, and the HRV&Hormonal parameters is 0,766. In turn, the immune parameters are closely related to the HRV&Hormonal parameters (R=0,714). Conclusion. Disturbances of the geomagnetic field (Ap-index) causes a significant immediate modulating effect on the immune, HRV and endocrine parameters, apparently through acupuncture points as polymodal receptors of the ecoceptive sensitivity system.

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46

Eun, Dong-Chan, Anthony A. Suguitan, Kyung-Soo Suk, Hak-Sun Kim, Ji-Won Kwon, Seong-Hwan Moon, Yong-Ho Lee, and Byung Ho Lee. "Variation in Prevertebral Soft Tissue Swelling after Staged Combined Multilevel Anterior–Posterior Complex Cervical Spine Surgery: Anterior Then Posterior (AP) versus Posterior Then Anterior–Posterior (PAP) Surgery." Journal of Clinical Medicine 11, no. 23 (December 6, 2022): 7250. http://dx.doi.org/10.3390/jcm11237250.

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The influence of the sequence of surgery in the development of prevertebral soft tissue swelling (PSTS) in staged combined multilevel anterior–posterior complex spine surgery was examined. This study was conducted as a retrospective study of patients who underwent staged combined multilevel anterior–posterior complex cervical spine surgery from March 2014 to February 2021. Eighty-two patients were identified, of which fifty-seven were included in the final analysis after screening. PSTS was measured from routine serial monitoring lateral cervical radiographs prior to and after surgery for five consecutive days at each cervical level from C2 to C7 in patients who underwent anterior then posterior (AP) and posterior then anterior–posterior (PAP) surgery. The mean PSTS measurements significantly differed from the preoperative to postoperative monitoring days at all cervical levels (p = 0.0000) using repeated measures analysis of variance in both groups. PSTS was significantly greater in PAP than in AP at level C2 on postoperative day (POD) 1 (p = 0.0001). PSTS was more prominent at levels C2–4 during PODs 2–4 for both groups. In staged combined multilevel anterior–posterior complex spine surgery, PSTS is an inevitable complication. Therefore, surgeons should monitor PSTS after surgery when performing anterior–posterior complex cervical spine surgery, especially in the immediate postoperative period after PAP surgery.

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47

Taimor, G., K. D. Schlüter, P. Best, S. Helmig та H. M. Piper. "Transcription activator protein 1 mediates α- but not β-adrenergic hypertrophic growth responses in adult cardiomyocytes". American Journal of Physiology-Heart and Circulatory Physiology 286, № 6 (червень 2004): H2369—H2375. http://dx.doi.org/10.1152/ajpheart.00741.2003.

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In some models of cardiac hypertrophy, activation of activator protein 1 (AP-1) correlates with growth. However, AP-1 is also activated by stimuli not involved in cardiac growth. This raises the following questions: does AP-1 plays a causal role for cardiomyocyte growth, and is this role model or stimulus dependent? We used a single model to address these questions, i.e., ventricular cardiomyocytes of adult rats, and two growth stimuli, i.e., α- and β-adrenoceptor agonists [10 μM phenylephrine (PE) and 1 μM isoprenaline (Iso), respectively]. After 1 h of stimulation with PE, mRNA expression of c-Fos and c-Jun was upregulated to 185 ± 32 and 132 ± 13% of control. Fos and Jun proteins formed the AP-1 complex. PE stimulated DNA binding activity of AP-1 to 165 ± 22% of control within 2 h and increased protein synthesis to 161 ± 27% of control and cross-sectional area to 126 ± 4% of control. Inhibition of AP-1 binding activity by cAMP response element (CRE) decoy oligonucleotides abolished both of these growth responses. Iso stimulated AP-1 binding activity to 203 ± 19% of control within 2 h and stimulated protein synthesis to 145 ± 17% of control. However, the growth effect of Iso was not abolished by CRE decoys: Iso increased protein synthesis to 158 ± 17% of control in the presence of CRE. In conclusion, AP-1 is a causal mediator of the α-adrenergic, but not the β-adrenergic, growth response of cardiomyocytes.

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48

Jordan, Catherine, Gregory Geisel, Julian E. Alecu, Bo Zhang, Mustafa Sahin, and Darius Ebrahimi-Fakhari. "Disease Severity and Motor Impairment Correlate With Health-Related Quality of Life in AP-4-Associated Hereditary Spastic Paraplegia." Neurology Genetics 7, no. 4 (July 20, 2021): e605. http://dx.doi.org/10.1212/nxg.0000000000000605.

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ObjectiveAP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset neurogenetic disease and mimic of cerebral palsy. Data on health-related quality of life (HRQoL) are lacking. To establish a metric for HRQoL and caregiver priorities, we used the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire to assess HRQoL in correlation with disease severity in 64 patients with AP-4-HSP.MethodsA cross-sectional analysis of caregiver-reported HRQoL was performed using the CPCHILD questionnaire in combination with a detailed clinical characterization.ResultsHRQoL was impaired in all domains in patients with AP-4-HSP (mean score: 59.6 ± 12.6 [SD]), with no significant difference between the 4 subtypes. Age, as a surrogate for disease duration, and Spastic Paraplegia Rating Scale scores, as an indicator for corticospinal tract dysfunction and motor impairment, correlated with lower CPCHILD scores (Pearson r = −0.31, p = 0.01 and r = −0.52, p < 0.0001, respectively). Patients with tetraplegia showed lower CPCHILD scores compared with individuals with diplegia or no spasticity. Wheelchair dependence reduced HRQoL in all domains. The presence of seizures, including medically refractory epilepsy, was not associated with lower CPCHILD scores. Standardized assessment of caregiver priorities identified several areas of high importance to HRQoL.ConclusionsWe show that the CPCHILD questionnaire, developed for use in children with cerebral palsy, can be used to assess HRQoL in patients with childhood-onset complex hereditary spastic paraplegia. HRQoL is reduced in patients with AP-4-HSP and correlates with the degree of motor impairment. These results provide a framework for medical decision making and a baseline for the future development of treatment guidelines and interventional trials.

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49

Ouzon-Shubeita, Hala, Hunmin Jung, Michelle H. Lee, Myong-Chul Koag, and Seongmin Lee. "Catalytic mechanism of the mismatch-specific DNA glycosylase methyl-CpG-binding domain 4." Biochemical Journal 477, no. 9 (May 5, 2020): 1601–12. http://dx.doi.org/10.1042/bcj20200125.

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Thymine:guanine base pairs are major promutagenic mismatches occurring in DNA metabolism. If left unrepaired, these mispairs can cause C to T transition mutations. In humans, T:G mismatches are repaired in part by mismatch-specific DNA glycosylases such as methyl-CpG-binding domain 4 (hMBD4) and thymine-DNA glycosylase. Unlike lesion-specific DNA glycosylases, T:G-mismatch-specific DNA glycosylases specifically recognize both bases of the mismatch and remove the thymine but only from mispairs with guanine. Despite the advances in biochemical and structural characterizations of hMBD4, the catalytic mechanism of hMBD4 remains elusive. Herein, we report two structures of hMBD4 processing T:G-mismatched DNA. A high-resolution crystal structure of Asp560Asn hMBD4-T:G complex suggests that hMBD4-mediated glycosidic bond cleavage occurs via a general base catalysis mechanism assisted by Asp560. A structure of wild-type hMBD4 encountering T:G-containing DNA shows the generation of an apurinic/apyrimidinic (AP) site bearing the C1′-(S)-OH. The inversion of the stereochemistry at the C1′ of the AP-site indicates that a nucleophilic water molecule approaches from the back of the thymine substrate, suggesting a bimolecular displacement mechanism (SN2) for hMBD4-catalyzed thymine excision. The AP-site is stabilized by an extensive hydrogen bond network in the MBD4 catalytic site, highlighting the role of MBD4 in protecting the genotoxic AP-site.

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Tserkovniuk, R., A. Gozhenko, T. Korolyshyn, M. Kovbasnyuk, V. Hubyts’kyi, V. Kikhtan, V. Fil та ін. "Relationships between geomagnetic Ар-indeх and parameters of the acupuncture points as well as neuroendocrine-immune complex in patients with its dysfunction". Journal of Education, Health and Sport 11, № 12 (30 грудня 2021): 405–32. http://dx.doi.org/10.12775/jehs.2021.11.12.034.

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Background. Back in 1990, YuP Limansky hypothesized acupuncture points (AP) as polymodal receptors of the ecoceptive sensitivity system. In the process of hypothesis development in 2003 an existence of separate functional system of regulation of electromagnetic balance of organism has been substantiated and a working conception of light therapy has been formulated. In line with this hypothesis, we set out to analyze the relationships between the disturbances of the geomagnetic field (Ap-index) and the electrical conductivity of a number of AP, on the one hand, and the parameters of the neuroendocrine-immune complex in patients with its dysfunction, on the other. Material and methods. The object of observation were 21 men (24-63 y) and 20 women (30-72 y) with neuroendocrine-immune complex dysfunction. Each patient was tested twice with an interval of 4 days. Retrospectively we recorded the geomagnetic Ap-Index on the day of testing and during the previous 7 days, using resource https://www.spaceweatherlive.com/. Recorded the electrical conductivity of 9 pairs of AP, electroencephalogram (EEG) and heart rate variability (HRV) parameters, determined the plasma level of cortisol, triiodothyronine and testosterone, the content of lymphocytes expressing CD3, CD4, CD25, CD8, CD22 and CD56 receptors, the serum level of circulating immune complexes, immunoglobulins classes M, G, A as well as C-reactive protein, IL-1β and IL-6. The state of phagocytic function of neutrophils estimated by microbial count and phagocytic and killing indices against Staphylococcus aureus and Escherichia coli. Results. During the week, the average level of Ap-index ranged from 7 to 13 nT. Maximum coefficients of multiple correlation with APs parameters were detected for Ap-index on 6 day before (R=0,552) and on the day of testing (R=0,470), with EEG parameters on the eve of registration (R=0,708) and on 6 day before its (R=0,685), with immunity parameters on the eve of blood sampling (R=0,768) and on 5 day before its (R=0,758), with HRV&Hormonal parameters on 2 (R=0,506) and 7 (R=0,403) days before testing. The canonical correlation between Ap-indices for 7 days before and on the day of testing, and the parameters APs is 0,661; EEG parameters is 0,886; HRV&Hormonal parameters is 0,766 and immunity parameters is 0,921. APs parameter are closely related to the EEG (R=0,997) and HRV&Hormonal parameters (R=0,740). In turn, the immune parameters are closely related to the EEG (R=0,944) and HRV&Hormonal parameters (R=0,714). Conclusion. Disturbances of the geomagnetic field (Ap-index) causes a significant immediate modulating effect on the parameters of neuroendocrine-immune complex, apparently through acupuncture points as polymodal receptors of the ecoceptive sensitivity system.

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