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Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.
The discovery of clustered regularly interspaced short palindromic repeats and their associated proteins (Cas) has revolutionized the field of genome and epigenome editing. A number of new methods have been developed to precisely control the function and activity of Cas proteins, including fusion proteins and small-molecule modulators. Proteolysis-targeting chimeras (PROTACs) represent a new concept using the ubiquitin-proteasome system to degrade a protein of interest, highlighting the significance of chemically induced protein-E3 ligase interaction in drug discovery. Here, we engineered Cas proteins (Cas9, dCas9, Cas12, and Cas13) by inserting a Phe-Cys-Pro-Phe (FCPF) amino acid sequence (known as the π-clamp system) and demonstrate that the modified CasFCPF proteins can be (1) labeled in live cells by perfluoroaromatics carrying the fluorescein or (2) degraded by a perfluoroaromatics-functionalized PROTAC (PROTAC-FCPF). A proteome-wide analysis of PROTAC-FCPF-mediated Cas9FCPF protein degradation revealed a high target specificity, suggesting a wide range of applications of perfluoroaromatics-induced proximity in the regulation of stability, activity, and functionality of any FCPF-tagging protein.
Background: One of the most popular and versatile model of murine melanoma is by inoculating B16 cells in the syngeneic C57BL6J mouse strain. A characterization of different B16 modified cell sub-lines will be of real practical interest. For this aim, modern analytical tools like surface enhanced Raman spectroscopy/scattering (SERS) and MTT were employed to characterize both chemical composition and proliferation behavior of the selected cells.
Methods: High quality SERS signal was recorded from each of the four types of B16 cell sub-lines: B164A5, B16GMCSF, B16FLT3, B16F10, in order to observe the differences between a parent cell line (B164A5) and other derived B16 cell sub-lines. Cells were incubated with silver nanoparticles of 50–100 nm diameter and the nanoparticles uptake inside the cells cytoplasm was proved by transmission electron microscopy (TEM) investigations. In order to characterize proliferation, growth curves of the four B16 cell lines, using different cell numbers and FCS concentration were obtained employing the MTT proliferation assay. For correlations doubling time were calculated.
Results: SERS bands allowed the identification inside the cells of the main bio-molecular components such as: proteins, nucleic acids, and lipids. An "on and off" SERS effect was constantly present, which may be explained in terms of the employed laser power, as well as the possible different orientations of the adsorbed species in the cells in respect to the Ag nanoparticles. MTT results showed that among the four tested cell sub-lines B16 F10 is the most proliferative and B164A5 has the lower growth capacity. Regarding B16FLT3 cells and B16GMCSF cells, they present proliferation ability in between with slight slower potency for B16GMCSF cells.
Conclusion: Molecular fingerprint and proliferation behavior of four B16 melanoma cell sub-lines were elucidated by associating SERS investigations with MTT proliferation assay.
Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR–ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 106, 1.08±0.11 × 105, 1.03±0.10 × 104, 1.02±0.09 × 103, 1.04±0.10 × 102 and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR–ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR–ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).
We have analyzed a series of eleven mutations in the 49-kDa protein of mitochondrial complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica to identify functionally important domains in this central subunit. The mutations were selected based on sequence homology with the large subunit of [NiFe] hydrogenases. None of the mutations affected assembly of complex I, all decreased or abolished ubiquinone reductase activity. Several mutants exhibited decreased sensitivities toward ubiquinone-analogous inhibitors. Unexpectedly, seven mutations affected the properties of iron-sulfur cluster N2, a prosthetic group not located in the 49-kDa subunit. In three of these mutants cluster N2 was not detectable by electron-paramagnetic resonance spectroscopy. The fact that the small subunit of hydrogenase is homologous to the PSST subunit of complex I proposed to host cluster N2 offers a straightforward explanation for the observed, unforeseen effects on this iron-sulfur cluster. We propose that the fold around the hydrogen reactive site of [NiFe] hydrogenase is conserved in the 49-kDa subunit of complex I and has become part of the inhibitor and ubiquinone binding region. We discuss that the fourth ligand of iron-sulfur cluster N2 missing in the PSST subunit may be provided by the 49-kDa subunit.
During early G1 phase, Rb is exclusively mono-phosphorylated by cyclin D:Cdk4/6, generating 14 different isoforms with specific binding patterns to E2Fs and other cellular protein targets. While mono-phosphorylated Rb is dispensable for early G1 phase progression, interfering with cyclin D:Cdk4/6 kinase activity prevents G1 phase progression, questioning the role of cyclin D:Cdk4/6 in Rb inactivation. To dissect the molecular functions of cyclin D:Cdk4/6 during cell cycle entry, we generated a single cell reporter for Cdk2 activation, RB inactivation and cell cycle entry by CRISPR/Cas9 tagging endogenous p27 with mCherry. Through single cell tracing of Cdk4i cells, we identified a time-sensitive early G1 phase specific Cdk4/6-dependent phosphorylation gradient that regulates cell cycle entry timing and resides between serum-sensing and cyclin E:Cdk2 activation. To reveal the substrate identity of the Cdk4/6 phosphorylation gradient, we performed whole proteomic and phospho-proteomic mass spectrometry, and identified 147 proteins and 82 phospho-peptides that significantly changed due to Cdk4 inhibition in early G1 phase. In summary, we identified novel (non-Rb) cyclin D:Cdk4/6 substrates that connects early G1 phase functions with cyclin E:Cdk2 activation and Rb inactivation by hyper-phosphorylation.
The pathophysiology of Takotsubo Syndrome (TTS) is not completely understood and the trigger of sudden cardiac death (SCD) in TTS is not clear either. We therefore sought to find an association between TTS and primary electrical diseases. A total of 148 TTS patients were analyzed between 2003 and 2017 in a bi-centric manner. Additionally, a literature review was performed. The patients were included in an ongoing retrospective cohort database. The coexistence of TTS and primary electrical diseases was confirmed in five cases as the following: catecholaminergic polymorphic ventricular tachycardia (CPVT, 18-year-old female) (n = 1), LQTS 1 (72-year-old female and 65-year-old female) (n = 2), LQTS 2 (17-year-old female) (n = 1), and LQTS in the absence of mutations (22-year-old female). Four patients suffered from malignant tachyarrhythmia and recurrent syncope after TTS. Except for the CPVT patient and one LQTS 1 patient, all other cases underwent subcutaneous ICD implantation. An event recorder of the CPVT patient after starting beta-blocker did not detect arrhythmias. The diagnosis of primary electrical disease was in 80% of cases unmasked on a TTS event. This diagnosis triggered a family clinical and genetic screening confirming the diagnosis of primary electrical disease. A subsequent literature review identified five cases as the following: a congenital atrioventricular block (n = 1), a Jervell and Lange-Nielsen Syndrome (n = 1), and a family LQTS in the absence of a mutation (n = 2), LQTS 2 (n = 1). A primary electrical disease should be suspected in young and old TTS patients with a family history of sudden cardiac death. In suspected cases, e.g., ongoing QT interval prolongation, despite recovery of left ventricular ejection fraction a family screening is recommended.
Vaccination represents one of the fundamentals in the fight against SARS-CoV-2. Myocarditis has been reported as a rare but possible adverse consequence of different vaccines, and its clinical presentation can range from mild symptoms to acute heart failure. We report a case of a 29-year-old man who presented with fever and retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance imaging and laboratory data revealed typical findings of acute myocarditis.
A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer
(2019)
Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions.
Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms.
Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.
At a site in the Bolivian Chiquitano region composed by a mosaic of pastureland and primary Chiquitano Dry Forest (CDF) we conducted a camera-trapping study to (1) survey the mammals, and (2) compare individual Jaguar numbers with other Chiquitano sites. Therefore, we installed 13 camera stations (450 ha polygon) over a period of six months. On 1,762 camera-days and in 1,654 independent capture events, we recorded 24 mammalian species that represent the native fauna of large and medium-sized mammals including apex-predators (Puma, Jaguar), meso-carnivores (Ocelot, Jaguarundi, Margay), and large herbivores (Tapir, Collared and White lipped Peccary). We identified six adult Jaguars and found indications of successful reproductive activity. Captures of Jaguars were higher in CDF than in altered habitats. In summary, we believe that (1) the mammal species richness, (2) the high capture numbers of indicator species, and (3) the high capture numbers of Jaguar indicate that our study area has a good conservation status. Future efforts should be undertaken to keep this, and monitoring programs in this region are necessary to further evaluate the potential importance of the Chiquitano region as a possible key region for mammals, especially Jaguars, in South America.
The most frequently used boundary-layer turbulence parameterization in numerical weather prediction (NWP) models are turbulence kinetic energy (TKE) based-based schemes. However, these parameterizations suffer from a potential weakness, namely the strong dependence on an ad-hoc quantity, the so-called turbulence length scale. The physical interpretation of the turbulence length scale is difficult and hence it cannot be directly related to measurements or large eddy simulation (LES) data. Consequently, formulations for the turbulence length scale in basically all TKE schemes are based on simplified assumptions and are model-dependent. A good reference for the independent evaluation of the turbulence length scale expression for NWP modeling is missing. Here we propose a new turbulence length scale diagnostic which can be used in the gray zone of turbulence without modifying the underlying TKE turbulence scheme. The new diagnostic is based on the TKE budget: The core idea is to encapsulate the sum of the molecular dissipation and the cross-scale TKE transfer into an effective dissipation, and associate it with the new turbulence length scale. This effective dissipation can then be calculated as a residuum in the TKE budget equation (for horizontal sub-domains of different sizes) using LES data. Estimation of the scale dependence of the diagnosed turbulence length scale using this novel method is presented for several idealized cases.
Knowledge discovery in biomedical data using supervised methods assumes that the data contain structure relevant to the class structure if a classifier can be trained to assign a case to the correct class better than by guessing. In this setting, acceptance or rejection of a scientific hypothesis may depend critically on the ability to classify cases better than randomly, without high classification performance being the primary goal. Random forests are often chosen for knowledge-discovery tasks because they are considered a powerful classifier that does not require sophisticated data transformation or hyperparameter tuning and can be regarded as a reference classifier for tabular numerical data. Here, we report a case where the failure of random forests using the default hyperparameter settings in the standard implementations of R and Python would have led to the rejection of the hypothesis that the data contained structure relevant to the class structure. After tuning the hyperparameters, classification performance increased from 56% to 65% balanced accuracy in R, and from 55% to 67% balanced accuracy in Python. More importantly, the 95% confidence intervals in the tuned versions were to the right of the value of 50% that characterizes guessing-level classification. Thus, tuning provided the desired evidence that the data structure supported the class structure of the data set. In this case, the tuning made more than a quantitative difference in the form of slightly better classification accuracy, but significantly changed the interpretation of the data set. This is especially true when classification performance is low and a small improvement increases the balanced accuracy to over 50% when guessing.
Child maltreatment remains a major health threat globally that requires the understanding of socioeconomic and cultural contexts to craft effective interventions. However, little is known about research agendas globally and the development of knowledge-producing networks in this field of study. This study aims to explore the bibliometric overview on child maltreatment publications to understand their growth from 1916 to 2018. Data from the Web of Science Core Collection were collected in May 2018. Only research articles and reviews written in the English language were included, with no restrictions by publication date. We analyzed publication years, number of papers, journals, authors, keywords and countries, and presented the countries collaboration and co-occurrence keywords analysis. From 1916 to 2018, 47,090 papers (53.0% in 2010–2018) were published in 9442 journals. Child Abuse & Neglect (2576 papers; 5.5%); Children and Youth Services Review (1130 papers; 2.4%) and Pediatrics (793 papers, 1.7%) published the most papers. The most common research areas were Psychology (16,049 papers, 34.1%), Family Studies (8225 papers, 17.5%), and Social Work (7367 papers, 15.6%). Among 192 countries with research publications, the most prolific countries were the United States (26,367 papers), England (4676 papers), Canada (3282 papers) and Australia (2664 papers). We identified 17 authors who had more than 60 scientific items. The most cited papers (with at least 600 citations) were published in 29 journals, headed by the Journal of the American Medical Association (JAMA) (7 papers) and the Lancet (5 papers). This overview of global research in child maltreatment indicated an increasing trend in this topic, with the world’s leading centers located in the Western countries led by the United States. We called for interdisciplinary research approaches to evaluating and intervening on child maltreatment, with a focus on low-middle income countries (LMICs) settings and specific contexts.
A Bayesian framework to estimate diversification rates and their variation through time and space
(2011)
Background: Patterns of species diversity are the result of speciation and extinction processes, and molecular phylogenetic data can provide valuable information to derive their variability through time and across clades. Bayesian Markov chain Monte Carlo methods offer a promising framework to incorporate phylogenetic uncertainty when estimating rates of diversification.
Results: We introduce a new approach to estimate diversification rates in a Bayesian framework over a distribution of trees under various constant and variable rate birth-death and pure-birth models, and test it on simulated phylogenies. Furthermore, speciation and extinction rates and their posterior credibility intervals can be estimated while accounting for non-random taxon sampling. The framework is particularly suitable for hypothesis testing using Bayes factors, as we demonstrate analyzing dated phylogenies of Chondrostoma (Cyprinids) and Lupinus (Fabaceae). In addition, we develop a model that extends the rate estimation to a meta-analysis framework in which different data sets are combined in a single analysis to detect general temporal and spatial trends in diversification.
Conclusions: Our approach provides a flexible framework for the estimation of diversification parameters and hypothesis testing while simultaneously accounting for uncertainties in the divergence times and incomplete taxon sampling.
The Wood-Ljungdahl pathway of anaerobic CO(2) fixation with hydrogen as reductant is considered a candidate for the first life-sustaining pathway on earth because it combines carbon dioxide fixation with the synthesis of ATP via a chemiosmotic mechanism. The acetogenic bacterium Acetobacterium woodii uses an ancient version of the pathway that has only one site to generate the electrochemical ion potential used to drive ATP synthesis, the ferredoxin-fueled, sodium-motive Rnf complex. However, hydrogen-based ferredoxin reduction is endergonic, and how the steep energy barrier is overcome has been an enigma for a long time. We have purified a multimeric [FeFe]-hydrogenase from A. woodii containing four subunits (HydABCD) which is predicted to have one [H]-cluster, three [2Fe2S]-, and six [4Fe4S]-clusters consistent with the experimental determination of 32 mol of Fe and 30 mol of acid-labile sulfur. The enzyme indeed catalyzed hydrogen-based ferredoxin reduction, but required NAD(+) for this reaction. NAD(+) was also reduced but only in the presence of ferredoxin. NAD(+) and ferredoxin reduction both required flavin. Spectroscopic analyses revealed that NAD(+) and ferredoxin reduction are strictly coupled and that they are reduced in a 1:1 stoichiometry. Apparently, the multimeric hydrogenase of A. woodii is a soluble energy-converting hydrogenase that uses electron bifurcation to drive the endergonic ferredoxin reduction by coupling it to the exergonic NAD(+) reduction.
A B-factor for NOEs?
(2022)
Nuclear Overhauser effects (NOEs) are influenced by motion. Here, we derive exact, analytical results for a model of isotropic, harmonic fluctuations of atom positions that corresponds to the one underlying crystallographic B-factors. The model includes steric repulsion and yields closed-form expressions for the expected value of general invertible functions of the distance between two atoms, with the special case r-6 for NOEs. We discuss the implications for the definition of an NOE-based B-factor in solution NMR.
Theodor W. Adorno publicou o ensaio “Teoria da semiformação” (Theorie der Halbbildung) em 1959. A partir da publicação deste texto, observou-se sua relevância, sobretudo para que se pudesse compreender a maneira como a indústria cultural determinava a produção de prejuízos significativos no processo formativo. Desde então, a conquista do espírito feita pelo caráter fetichista dos produtos da indústria cultural, sendo esta uma das definições de Adorno sobre o conceito de Halbbildung, impulsionou a realização de muitas pesquisas sobre os danos decorrentes desta conquista na formação. Porém, investigar as atuais características do processo semiformativo não resulta na aplicação direta dos conceitos propostos por Adorno no final da década de 1950. Sendo assim, é preciso que tais conceitos sejam revitalizados por meio da análise das atuais mediações históricas. Seguindo essa linha de raciocínio, o principal objetivo deste artigo é argumentar que a reflexão crítica sobre o modo como a semiformação se renova, na atual sociedade da chamada cultura digital, torna-se fundamental para que se possam elaborar considerações sobre o renascimento da formação (Bildung).
Este ensaio vem problematizar acerca da atualidade do conceito de indústria cultural (Kulturindustrie), no projeto da teoria crítica de Theodor W. Adorno, objetivando mostrar que as atuais limitações impostas ao debate derivam mais do fundamento não-dialético dos que apontam sua restrição do que da própria potência da teorização frankfurtiana.
A atualidade da crítica de Adorno para as pesquisas qualitativas com bases empíricas em educação
(2018)
Neste artigo, serão apresentados dados e argumentos sobre a atualidade da crítica de Theodor W. Adorno para as pesquisas qualitativas com bases empíricas em educação, com especial ênfase à hermenêutica objetiva, desenvolvida por Ulrich Oevermann e aplicada por Andreas Gruschka às pesquisas em educação. O tema será abordado da seguinte maneira: (a) serão apontados elementos históricos e teóricos do desenvolvimento de um método de pesquisa próprio pela Teoria Crítica; (b) serão apresentados elementos caracterizadores da hermenêutica objetiva; (c) para, por fim, apresentar algumas das contribuições de Gruschka na aplicabilidade do referido método às pesquisas educacionais na Alemanha, além de algumas experiências no Brasil a partir da referida abordagem de pesquisa.
O objetivo do texto é propor uma interpretação do conceito de sublime na Teoria estética de Theodor Adorno, partindo do confronto com leituras significativas de outros comentadores, de modo a fornecer uma concepção que associe o movimento de transcendência e alteridade da forma estética à dinâmica histórico-processual das obras.