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In this feature article, we discuss the fundamental use of materials-characterization methods that directly determine structural information on the dye···TiO2 interface in dye-sensitized solar cells (DSCs). This interface is usually buried within the DSC and submerged in solvent and electrolyte, which renders such metrological work nontrivial. We will show how ex-situ X-ray reflectometry (XRR), atomic-force microscopy (AFM), grazing-incidence X-ray scattering (GIXS), pair-distribution-function analysis of X-ray diffraction data (gaPDF), and in-situ neutron reflectometry (NR) can be used to deliver specific structural information on the dye···TiO2 interface regarding dye anchoring, dye aggregation, molecular dye orientation, intermolecular spacing between dye molecules, interactions between the dye molecules and the TiO2 surface, and interactions between the dye molecules and the electrolyte components and precursors. Some of these materials-characterization techniques have been developed specifically for this purpose. We will demonstrate how the direct acquisition of such information from materials-characterization experiments is crucial for assembling a holistic structural picture of this interface, which in turn can be used to develop DSC design guidelines. Moreover, we will show how these methodologies can be used in the experimental-validation process of "design-to-device" pipelines for big-data- and machine-learning-based materials discovery. We conclude with an outlook on further developments of this design-to-device approach as well as the materials characterization of more dye···TiO2 interfacial structures that involve known DSC dyes using the methods described herein. In addition, we propose to combine these formally disparate metrologies so that their complementary merits can be exploited simultaneously. New metrologies of this kind could serve as a "one-stop-shop" for the materials characterization of surfaces, interfaces, and bulk structures in DSCs and other devices with layered architectures.
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We make the case for benzo[c]quinolin-6-ylidene (1) as a strongly electron-donating carbene ligand. The facile synthesis of 6-trifluoromethanesulfonylbenzo[c]quinolizinium trifluoromethanesulfonate (2) gives straightforward access to a useful precursor for oxidative addition to low-valent metals, to yield the desired carbene complexes. This concept has been achieved in the case of [Mn(benzo[c]quinolin-6-ylidene)(CO)5](+) (15) and [Pd(benzo[c]quinolin-6-ylidene)(PPh3)2(L)](2+) L = THF (21), OTf (22) or pyridine (23). Attempts to coordinate to nickel result in coupling products from two carbene precursor fragments. The CO IR-stretching-frequency data for the manganese compound suggests benzo[c]quinolin-6-ylidene is at least as strong a donor as any heteroatom-stabilised carbene ligand reported.
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The authors present the case of a 14-year-old boy who died while handling a crossbow, which was a gift from a friend's mother. The bolt passed through the right nostril, penetrated the sinus sphenoidalis, the brain stem, the left occipital lobe and the occipital calvaria. Immediately after the accident, the victim was taken to a maximum care hospital. In spite of neurosurgical treatment and intensive care the victim died 4 days later. The case presented demonstrates that crossbows are not suitable as toys for underage persons, as they are deadly weapons which can cause serious penetrating injuries. In Germany, no license is required to buy and/or possess crossbows. In the authors' opinion, legal restrictions on the sale of crossbows and a special training of the users would be reasonable measures to reduce such accidents.
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Lesões Encefálicas/patologia , Homicídio/legislação & jurisprudência , Jogos e Brinquedos , Fraturas Cranianas/patologia , Armas/legislação & jurisprudência , Ferimentos Penetrantes/patologia , Adolescente , Morte Encefálica , Lesões Encefálicas/cirurgia , Craniotomia , Evolução Fatal , Alemanha , Humanos , Hemorragia Intracraniana Traumática/patologia , Hemorragia Intracraniana Traumática/cirurgia , Hipertensão Intracraniana/patologia , Hipertensão Intracraniana/cirurgia , Masculino , Reoperação , Fraturas Cranianas/cirurgia , Tomografia Computadorizada por Raios X , Ferimentos Penetrantes/cirurgiaRESUMO
BACKGROUND: Superinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of critically ill patients with severe viral pneumonia. Aim of this study was to evaluate the incidence, risk factors and outcome of IPA in critically ill patients with severe COVID-19 pneumonia. METHODS: We prospectively screened 32 critically ill patients with severe COVID-19 pneumonia for a time period of 28 days using a standardized study protocol for oberservation of developement of COVID-19 associated invasive pulmonary aspergillosis (CAPA). We collected laboratory, microbiological, virological and clinical parameters at defined timepoints in combination with galactomannan-antigen-detection from nondirected bronchial lavage (NBL). We used logistic regression analyses to assess if COVID-19 was independently associated with IPA and compared it with matched controls. FINDINGS: CAPA was diagnosed at a median of 4 days after ICU admission in 11/32 (34%) of critically ill patients with severe COVID-19 pneumonia as compared to 8% in the control cohort. In the COVID-19 cohort, mean age, APACHE II score and ICU mortality were higher in patients with CAPA than in patients without CAPA (36% versus 9.5%; p<0.001). ICU stay (21 versus 17 days; p = 0.340) and days of mechanical ventilation (20 versus 15 days; p = 0.570) were not different between both groups. In regression analysis COVID-19 and APACHE II score were independently associated with IPA. INTERPRETATION: CAPA is highly prevalent and associated with a high mortality rate. COVID-19 is independently associated with invasive pulmonary aspergillosis. A standardized screening and diagnostic approach as presented in our study can help to identify affected patients at an early stage.
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COVID-19/complicações , Aspergilose Pulmonar Invasiva/etiologia , Pneumonia Viral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar/microbiologia , Líquido da Lavagem Broncoalveolar/virologia , COVID-19/microbiologia , COVID-19/virologia , Estado Terminal , Feminino , Galactose/análogos & derivados , Humanos , Unidades de Terapia Intensiva , Aspergilose Pulmonar Invasiva/microbiologia , Aspergilose Pulmonar Invasiva/virologia , Masculino , Mananas/metabolismo , Pessoa de Meia-Idade , Pneumonia Viral/microbiologia , Pneumonia Viral/virologia , Estudos Prospectivos , Respiração Artificial/métodos , SARS-CoV-2/patogenicidade , Superinfecção/etiologia , Superinfecção/microbiologiaRESUMO
PURPOSE: Sudden unilateral peripheral vestibular deficit is mostly termed vestibular neuritis (VN), even if its cause or the exact location of the lesion remains unclear. Thus, therapy is mostly symptomatic. We aimed to prove if there is peripheral atrophy after VN with persistent canal paresis. METHODS: After approval by the ethics committee and according to the declaration of Helsinki and with informed consent, ten patients with persistent canal paresis after VN and ten age-matched healthy controls were included. High-resolution measurement (in-plane resolution 0.2âmm) of the internal auditory canal (IAC) using a 3âD CISS sequence at 3 Tesla was performed. The course of the pertaining nerves was reconstructed in the 3âD dataset and the measurement was performed at 60â% of the length of the IAC. The cross-sectional areas of the superior (SVN) and inferior vestibular nerve (IVN) were taken independently by two blinded readers. RESULTS: The interrater difference regarding the area was 22â%. We found significant atrophy of the SVN with a 24â% smaller area (pâ=â0.026) and found a smaller ratio of SVN/IVN on the symptomatic side (pâ=â0.017). Concerning single subject data, only 5 patients showed extensive atrophy of the NVS, while 5 patients did not. The time since symptom onset did not significantly influence the atrophy. CONCLUSION: MRI measuring of the area of the NVS after VN could detect atrophy after VN. However, only 5 patients exhibited marked atrophy, while the other 5 patients did not. With the background of stringent inclusion criteria (more than 6 months of symptom duration and proven persistent canal paresis), one has to wonder if there might be different etiologies behind the apparently identical symptoms. KEY POINTS: · MRI measuring of the area of the NVS after VN could detect atrophy after VN. · Only half of the 10 researched patients showed atrophy, while the other patients did not. · There are different etiologies to be suspected for VN. CITATION FORMAT: · Freund W, Weber F, Schneider D etâal. Vestibular Nerve Atrophy After Vestibular Neuritis - Results from a Prospective High-Resolution MRI Study. Fortschr Röntgenstr 2020; 192: 854â-â861.
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Inteligência Artificial , Aumento da Imagem , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Nervo Vestibular/diagnóstico por imagem , Neuronite Vestibular/diagnóstico por imagem , Algoritmos , Atrofia , Meato Acústico Externo/diagnóstico por imagem , Meato Acústico Externo/patologia , Humanos , Estudos Prospectivos , Nervo Vestibular/patologiaRESUMO
Olfactory sensory neurons expose to the inhaled air chemosensory cilia which bind odorants and operate as transduction organelles. Odorant receptors in the ciliary membrane activate a transduction cascade which uses cAMP and Ca(2+) for sensory signaling in the ciliary lumen. Although the canonical transduction pathway is well established, molecular components for more complex aspects of sensory transduction, like adaptation, regulation, and termination of the receptor response have not been systematically identified. Moreover, open questions in olfactory physiology include how the cilia exchange solutes with the surrounding mucus, assemble their highly polarized set of proteins, and cope with noxious substances in the ambient air. A specific ciliary proteome would promote research efforts in all of these fields. We have improved a method to detach cilia from rat olfactory sensory neurons and have isolated a preparation specifically enriched in ciliary membrane proteins. Using LC-ESI-MS/MS analysis, we identified 377 proteins which constitute the olfactory cilia proteome. These proteins represent a comprehensive data set for olfactory research since more than 80% can be attributed to the characteristic functions of olfactory sensory neurons and their cilia: signal processing, protein targeting, neurogenesis, solute transport, and cytoprotection. Organellar proteomics thus yielded decisive information about the diverse physiological functions of a sensory organelle.
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Cílios/química , Neurônios Receptores Olfatórios/química , Proteínas/química , Proteoma , Receptores Odorantes/química , Adenilil Ciclases/química , Adenilil Ciclases/metabolismo , Animais , Cromatografia Líquida , Cílios/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/química , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Bases de Dados de Proteínas , Isoenzimas/química , Isoenzimas/metabolismo , Microscopia Eletrônica de Varredura , Mucosa Olfatória/anatomia & histologia , Neurônios Receptores Olfatórios/metabolismo , Proteínas/metabolismo , Ratos , Ratos Wistar , Receptores Odorantes/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em TandemRESUMO
Water-soluble, high-molecular-weight polycobaltocenium polyelectrolytes have been prepared by ring-opening polymerization (ROP) techniques. Anionic polymerization of a strained 19-electron dicarba[2]cobaltocenophane followed by oxidation in the presence of ammonium chloride resulted in the formation of oligomers with up to nine repeat units. Thermal ROP of dicarba[2]cobaltocenophane followed by oxidation in the presence of ammonium nitrate resulted in the formation of high-molecular-weight polycobaltocenium nitrate, a redox-active cobalt-containing polyelectrolyte.
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The ring-opening polymerization (ROP) behavior of a variety of substituted 1,1'-ethylenylferrocenes, or dicarba[2]ferrocenophanes, is reported. The electronic absorption spectra and tilted solid-state structures of the monomers rac-[Fe(eta(5)-C(5)H(4))(2)(CHiPr)(2)] (7), [Fe(eta(5)-C(5)H(4))(2)(C(H)MeCH(2))] (8), and rac-[Fe(eta(5)-C(5)H(4))(2)(CHPh)(2)] (9) are consistent with the presence of substantial ring strain, which was exploited to synthesize soluble, well-defined polyferrocenylethylenes (PFEs) [Fe(eta(5)-C(5)H(4))(2)(C(H)MeCH(2))](n) (12) and [Fe(eta(5)-C(5)H(4))(2)(CHPh)(2)](n) (13) through photocontrolled ROP. Polymer chain lengths could be controlled by the monomer-to-initiator ratio up to about 50 repeat units and, consistent with the "living" nature of the polymerizations, sequential block copolymerization with a sila[1]ferrocenophane led to polyferrocenylethylene-polyferrocenylsilane (PFE-b-PFS) block copolymers (14 and 15). PFE polymers 12 and 13 showed two reversible oxidation waves, indicative of appreciable FeFe interactions along the polymer backbone. The diblock copolymers were characterized by NMR spectroscopy, GPC analysis, and cyclic voltammetry.
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The structures, bonding, and ring-opening reactions of strained cyclic carbon-based molecules form a key component of standard textbooks. In contrast, the study of strained organometallic molecules containing transition metals is a much more recent development. A wealth of recent research has revealed fascinating nuances in terms of structure, bonding, and reactivity. Building on initial work on strained ferrocenophanes, a broad range of strained organometallic rings composed of a variety of different metals, pi-hydrocarbon ligands, and bridging elements has now been developed. Such strained species can potentially undergo ring-opening reactions to functionalize surfaces and ring-opening polymerization to form easily processed metallopolymers with properties determined by the presence of the metal and spacer. This Review summarizes the current state of knowledge on the preparation, structural characterization, electronic structure, and reactivity of strained organometallic rings with pi-hydrocarbon ligands and d-block metals.
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PURPOSE: Couch-mounted cone-beam computed tomography (CBCT) imaging devices with independently rotatable x-ray source and flat-panel detector arms for acquisitions of arbitrary regions of interest (ROI) have recently been introduced in image-guided radiotherapy (IGRT). This work analyzes mechanical limitations and gravity-induced effects influencing the geometric accuracy of images acquired with arbitrary angular constellations of source and detector in nonisocentric trajectories, which is considered essential for IGRT. In order to compensate for geometric inaccuracies of this modality, a 9-degrees-of-freedom (9-DOF) flexmap correction approach is presented, focusing especially on the separability of the flexmap parameters of the independently movable components of the device. METHODS: The 9-DOF comprise a 3D translation of the x-ray source focal spot, a 3D translation of the flat-panel's active area center and three Euler-rotations of the detector's row and column vectors. The flexmap parameters are expressed with respect to the angular position of each of the devices arms. Estimation of the parameters is performed, using a CT-based structure set of a table-mounted, cylindrical ball-bearing phantom. Digitally reconstructed radiograph (DRR) patches are derived from the structure set followed by local 2D in-plane registration and subsequent 3D transform estimation by nonlinear regression with outlier detection. RESULTS: Flexmap parameter evaluations for the factory-calibrated system in clockwise and counter-clockwise rotation direction have shown only minor differences for the overall set of flexmap parameters. High short-term reproducibility of the flexmap parameters has been confirmed by experiments over 10 acquisitions for both directions, resulting in standard deviation values of ≤0.183 mm for translational components and ≤0.0219 deg for rotational components, respectively. A comparison of isocentric and nonisocentric flexmap evaluations showed that the mean differences of the parameter curves reside within their standard deviations, confirming the ability of the proposed calibration method to handle both types of trajectories equally well. Reconstructions of 0.1 mm and 0.25 mm steel wires showed similar results for the isocentric and nonisocentric cases. The full-width at half maximum (FWHM) measure indicates an average improvement of the calibrated reconstruction of 85% over the uncalibrated reconstruction. The contrast of the point spread function (PSF) improved by 310% on average over all experiments. Moreover, a reduced amount of artifacts visible in nonisocentric reconstructions of a head phantom and a line-pair phantom has been achieved by separate application of the 9-DOF flexmap on the geometry described by the independently moving source arm and detector arm. CONCLUSIONS: Using a 9-DOF flexmap approach for correcting the geometry of projections acquired with a device capable of independent movements of the source and panel arms has been shown to be essential for IGRT use cases such as CBCT reconstruction and 2D/3D registration tasks. The proposed pipeline is able to create flexmap curves which are easy to interpret, useful for mechanical description of the device and repetitive quality assurance as well as system-level preventive maintenance. Application of the flexmap has shown improvements of image quality for planar imaging and volumetric imaging which is crucial for patient alignment accuracy.
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Tomografia Computadorizada de Feixe Cônico/instrumentação , Movimento (Física) , Processamento de Imagem Assistida por Computador , Reprodutibilidade dos TestesRESUMO
PURPOSE: The extensive and unpredictable biliary excretion of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G) may contribute to the wide interpatient variability reported in the disposition and gastrointestinal toxicity of CPT-11. We studied the role of P-glycoprotein (P-gp) in in vivo biliary excretion of CPT-11, SN-38 and SN-38G in mice lacking mdr1-type P-gp [ mdr1a/1b(-/-)] in the presence of the multidrug resistance (MDR) reversal agent, PSC833. METHODS: Wild-type (Wt) and mdr1a/1b(-/-) mice ( n=3 or 4) were treated intragastrically with PSC833 (50 mg/kg) or vehicle 2 h prior to i.v. CPT-11 dosing (10 mg/kg), and bile samples were collected. RESULTS AND CONCLUSIONS: P-gp was found to play an important role in CPT-11 biliary excretion, as there was a significant (40%, P<0.05) decrease in its biliary recovery in 90 min in mdr1a/1b(-/-) mice (6.6+/-0.6% dose) compared with Wt mice (11+/-1.2%). This also implied a major role of other undetermined non-P-gp-mediated mechanism(s) for hepatic transport of CPT-11, which was inhibited by PSC833 (1.8+/-0.8% with PSC833, 6.6+/-0.6% without PSC833) in mdr1a/1b(-/-) mice. SN-38 and SN-38G biliary transport was unchanged in mice lacking P-gp after vehicle treatment, indicating a lack of P-gp mediation in their transport. PSC833 significantly reduced (56-89%) SN-38 and SN-38G biliary transport in Wt and mdr1a/1b(-/-) mice, suggesting that PSC833 may be a candidate to modulate biliary excretion of SN-38 with potential use in reducing CPT-11 toxicity.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos Fitogênicos/farmacocinética , Bile/metabolismo , Camptotecina/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico , Camptotecina/análogos & derivados , Feminino , Glucuronídeos/metabolismo , Irinotecano , CamundongosRESUMO
Collagenase Clostridium histolyticum (CCH) contains a fixed ratio of class I (AUX-I) and class II (AUX-II) collagenases and is used as treatment for Dupuytren's contracture. These two Zn-dependent enzymes, produced by the Gram-positive bacterium Clostridium histolyticum, are related functionally to matrix metalloproteinases (MMPs) which, among other functions, degrade the extracellular matrix. Since AUX-I and AUX-II exhibit sequence similarities to human MMPs, we assessed MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3) for cross-reactivity with anti-AUX-I and anti-AUX-II antibodies in patient serum. Serum samples from 71 subjects enrolled in a long-term clinical study (58 males and 13 females; 63 ± 10 years old [mean ± standard error]) were evaluated for cross-reactivity with the five MMPs using the two validated enzyme-linked immunosorbent assays (ELISAs). Inhibition cutoff points for anti-AUX-I and anti-AUX-II antibodies were based on assay inhibition obtained with a nonspecific protein, bovine gamma globulin, which was tested for each clinical sample. No MMP cross-reactivity was found for any of the 71 clinical antibody-positive sera evaluated. Sequence identity assessments indicated minimal, nonmeaningful alignments of the MMPs and AUX-I/AUX-II. Furthermore, clinical adverse event assessments indicated no safety signals related to MMP inhibition. The bioanalytical results, sequence identity, and clinical assessments consistently did not demonstrate cross-reactivity between CCH antidrug antibodies and endogenous human matrix metalloproteinases. The results presented here suggest that treatment of Dupuytren's contracture patients with CCH does not lead to any clinical adverse events associated with MMP inhibition.
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Anticorpos Antibacterianos/sangue , Reações Cruzadas , Contratura de Dupuytren/imunologia , Metaloproteinases da Matriz/imunologia , Colagenase Microbiana/imunologia , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Homologia de Sequência de AminoácidosRESUMO
UNLABELLED: Proteomic studies often produce sets of hundreds of proteins. Bioinformatic information for these large protein sets must be collected from multiple online resources. Protein Information Crawler (PIC) automatically bulk-collects such data from multiple databases and prediction servers, based on National Center for Biotechnology Information (NCBI) gi numbers or accession numbers, and summarizes them in a Microsoft Excel spreadsheet and/or HTML table. PIC greatly accelerates information procurement, helps to build customized protein information databases and drastically reduces manual database investigation in extensive proteomic studies. AVAILABILITY: http://www.zoo.uni-heidelberg.de/mfa/PIC.
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Bases de Dados de Proteínas , Proteínas/química , Software , Biologia Computacional , Internet , Proteínas/classificação , Alinhamento de SequênciaRESUMO
The cilia of mammalian olfactory receptor neurons (ORNs) represent the sensory interface that is exposed to the air within the nasal cavity. The cilia are the site where odorants bind to specific receptors and initiate olfactory transduction that leads to excitation of the neuron. This process involves a multitude of ciliary proteins that mediate chemoelectrical transduction, amplification, and adaptation of the primary sensory signal. Many of these proteins were initially identified by their enzymatic activities using a membrane protein preparation from olfactory cilia. This so-called "calcium-shock" preparation is a versatile tool for the exploration of protein expression, enzyme kinetics, regulatory mechanisms, and ciliary development. To support such studies, we present a first proteomic analysis of this membrane preparation. We subjected the cilia preparation to liquid chromatography-electrospray ionisation (LC-ESI-MS/MS) tandem mass spectrometry and identified 268 proteins, of which 49% are membrane proteins. A detailed analysis of their cellular and subcellular localization showed that the cilia preparation obtained by calcium shock not only is highly enriched in ORN proteins but also contains a significant amount of nonciliary material. Although our proteomic study does not identify the entire set of ciliary and nonciliary proteins, it provides the first estimate of the purity of the calcium-shock preparation and provides valuable biochemical information for further research.
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Cílios/química , Proteínas de Membrana/análise , Mucosa Olfatória/química , Neurônios Receptores Olfatórios/química , Proteínas/análise , Proteômica , Animais , Cromatografia Líquida , Biologia Computacional , Proteínas de Membrana/isolamento & purificação , Mucosa Olfatória/citologia , Neurônios Receptores Olfatórios/ultraestrutura , Ratos , Ratos Wistar , Olfato , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Some new bulky fluorinated diphosphines have been prepared and converted to palladium dichloride complexes that have been found to give increased regioselectivity and activity over other Pd-diphosphine systems when used as catalysts for hydroxycarbonylation of styrene.
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Macrophages and myeloid dendritic cells (DCs) represent alternative differentiation options of bone marrow progenitors and blood monocytes. This choice profoundly influences the immune response under normal and pathological conditions, but the underlying transcriptional events remain unresolved. Here, we show that experimental activation of the transcription factors PU.1 and MafB in transformed chicken myeloid progenitors triggered alternative DC or macrophage fate, respectively. PU.1 activation also was instructive for DC fate in the absence of cytokines in human HL-60 cell-derived myeloid progenitor and monocyte clones. Differentiation of normal human monocytes to DCs led to a rapid increase of PU.1 to high levels that preceded phenotypic changes, but no MafB expression, whereas monocyte-derived macrophages expressed MafB and only moderate levels of PU.1. DCs inducing levels of PU.1 inhibited MafB expression in monocytes, which appeared to be required for DC specification, since constitutive MafB expression inhibited DC differentiation. Consistent with this, PU.1 directly bound to MafB, inhibited its transcriptional activity in macrophages, and repressed its ability to induce macrophage differentiation in chicken myeloid progenitors. We propose that high PU.1 activity favors DCs at the expense of macrophage fate by inhibiting expression and activity of the macrophage factor MafB.
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Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/citologia , Macrófagos/citologia , Proteínas Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Embrião de Galinha , Galinhas , Proteínas de Ligação a DNA/genética , Células Dendríticas/fisiologia , Regulação para Baixo/imunologia , Células Precursoras de Granulócitos/citologia , Células Precursoras de Granulócitos/fisiologia , Células HL-60 , Humanos , Macrófagos/fisiologia , Fator de Transcrição MafB , Monócitos/citologia , Monócitos/fisiologia , Proteínas Oncogênicas/genética , Fenótipo , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Fatores de Transcrição/genética , Transcrição Gênica/imunologia , Transformação GenéticaRESUMO
Most transcriptional repression pathways depend on the targeted deacetylation of histone tails. In this report, we characterize NIR, a novel transcriptional corepressor with inhibitor of histone acetyltransferase (INHAT) activity. NIR (Novel INHAT Repressor) is ubiquitously expressed throughout embryonic development and adulthood. NIR is a potent transcriptional corepressor that is not blocked by histone deacetylase inhibitors and is capable of silencing both basal and activator-driven transcription. NIR directly binds to nucleosomes and core histones and prevents acetylation by histone acetyltransferases, thus acting as a bona fide INHAT. Using a tandem affinity purification approach, we identified the tumor suppressor p53 as a NIR-interacting partner. Association of p53 and NIR was verified in vitro and in vivo. Upon recruitment by p53, NIR represses transcription of both p53-dependent reporters and endogenous target genes. Knock-down of NIR by RNA interference significantly enhances histone acetylation at p53-regulated promoters. Moreover, p53-dependent apoptosis is robustly increased upon depletion of NIR. In summary, our findings describe NIR as a novel INHAT that plays an important role in the control of p53 function.