Publications by authors named "Anna Czarna"

29 Publications

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Communal collective narcissism.

J Pers 2021 Apr 8. Epub 2021 Apr 8.

Faculty of Psychology, University of Warsaw, Warsaw, Poland.

Objectives: We aimed to introduce, validate, and showcase the utility of a new construct: communal collective narcissism.

Method: We conducted four studies, in which we developed a new scale for communal collective narcissism (Study 1, N = 856), tested the construct's unique predictions (Study 2, N = 276), examined its social relevance (Study 3, N = 250), and assessed its implications for intergroup outcomes (Study 4, N = 664).

Results: In Study 1, we verified the structural soundness of the Communal Collective Narcissism Inventory. In Study 2, we obtained evidence for a defining feature of communal collective narcissism, namely, that it predicts communal, but not agentic, ingroup-enhancement. In Study 3, we illustrated the social relevance of communal collective narcissism. Communal collective narcissists derogated outgroup members, if those outgroups threatened the ingroup and the threat targeted the ingroup's communion. Finally, in Study 4, we showed that communal collective narcissism predicts intergroup outcomes in the communal domain (e.g., humanitarian aid) better than agentic collective narcissism does, whereas agentic collective narcissism predicts intergroup outcomes in the agentic domain (i.e., preferences for military aggression) better than communal collective narcissism does.

Conclusions: The construct of communal collective narcissism is conceptually and empirically distinct from classic (i.e., agentic) collective narcissism.
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http://dx.doi.org/10.1111/jopy.12636DOI Listing
April 2021

Dually regulating the proliferation and the immune microenvironment of melanoma via nanoparticle-delivered siRNA targeting onco-immunologic CD155.

Biomater Sci 2020 Dec 22;8(23):6683-6694. Epub 2020 Oct 22.

Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou 510006, P.R. China.

Studies have shown that the simultaneous regulation of tumor cell proliferation and the suppressive tumor immune microenvironment (TIME) could achieve better therapeutic effects. However, the targets of the proliferation and the TIME are different, which greatly limits the development of cancer therapy. A recent study found CD155, a highly expressed poliovirus receptor in melanoma cells and melanoma-infiltrating macrophages, functions as both an oncogene and immune checkpoint. Thus, it is supposed that targeting CD155 could bring dual therapeutic effects. Herein, we propose silencing the CD155 of melanoma cells and melanoma-infiltrating macrophages by a nanoparticle-delivered small interference RNA (siRNA) targeting CD155 (siCD155). We encapsulated siCD155 into cationic lipid-assisted nanoparticles (CLAN) and demonstrated that the intravenous injection of CLAN could efficiently deliver siCD155 into melanoma cells and melanoma-infiltrating macrophages. The downregulation of CD155 in melanoma cells directly inhibited their proliferation, and meanwhile, the downregulation of CD155 in melanoma-infiltrating macrophages increased the activation of NK cells and T cells. Owing to this dual effect, CLAN significantly inhibited the growth of B16-F10 melanoma. Our study suggests that nanoparticle-delivered siCD155 may be a simple but effective strategy for inhibiting tumor proliferation and reprogramming TIME.
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http://dx.doi.org/10.1039/d0bm01420fDOI Listing
December 2020

An All-in-One Nanomedicine Consisting of CRISPR-Cas9 and an Autoantigen Peptide for Restoring Specific Immune Tolerance.

ACS Appl Mater Interfaces 2020 Oct 19;12(43):48259-48271. Epub 2020 Oct 19.

Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China.

Nanotechnology has shown great promise in treating diverse diseases. However, developing nanomedicines that can cure autoimmune diseases without causing systemic immunosuppression is still quite challenging. Herein, we propose an all-in-one nanomedicine comprising an autoantigen peptide and CRISPR-Cas9 to restore specific immune tolerance by engineering dendritic cells (DCs) into a tolerogenic phenotype, which can expand autoantigen-specific regulatory T (Treg) cells. In brief, we utilized cationic lipid-assisted poly(ethylene glycol)--poly(lactide--glycolide) (PEG-PLGA) nanoparticles to simultaneously encapsulate an autoimmune diabetes-relevant peptide (2.5mi), a CRISPR-Cas9 plasmid (pCas9), and three guide RNAs (gRNAs) targeting costimulatory molecules (CD80, CD86, and CD40). We demonstrated that the all-in-one nanomedicine was able to effectively codeliver these components into DCs, followed by simultaneous disruption of the three costimulatory molecules and presentation of the 2.5mi peptide on the genome-edited DCs. The resulting tolerogenic DCs triggered the generation and expansion of autoantigen-specific Treg cells by presenting the 2.5mi peptide to CD4 T cells in the absence of costimulatory signals. Using autoimmune type 1 diabetes (T1D) as a typical disease model, we demonstrated that our nanomedicine prevented autoimmunity to islet components and inhibited T1D development. Our all-in-one nanomedicine achieved codelivery of CRISPR-Cas9 and the peptide to DCs and could be easily applied to other autoimmune diseases by substitution of different autoantigen peptides.
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http://dx.doi.org/10.1021/acsami.0c10885DOI Listing
October 2020

Rational designs of in vivo CRISPR-Cas delivery systems.

Adv Drug Deliv Rev 2021 01 21;168:3-29. Epub 2019 Nov 21.

Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, PR China; Key Laboratory of Biomedical Engineering of Guangdong Province, and Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, PR China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, PR China. Electronic address:

The CRISPR-Cas system initiated a revolution in genome editing when it was, for the first time, demonstrated success in the mammalian cells. Today, scientists are able to readily edit genomes, regulate gene transcription, engineer posttranscriptional events, and image nucleic acids using CRISPR-Cas-based tools. However, to efficiently transport CRISPR-Cas into target tissues/cells remains challenging due to many extra- and intra-cellular barriers, therefore largely limiting the applications of CRISPR-based therapeutics in vivo. In this review, we summarize the features of plasmid-, RNA- and ribonucleoprotein (RNP)-based CRISPR-Cas therapeutics. Then, we survey the current in vivo delivery systems. We specify the requirements for efficient in vivo delivery in clinical settings, and highlight both efficiency and safety for different CRISPR-Cas tools.
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http://dx.doi.org/10.1016/j.addr.2019.11.005DOI Listing
January 2021

What do highly narcissistic people think and feel about (their) intelligence?

J Pers 2020 08 5;88(4):703-718. Epub 2019 Nov 5.

Institute of Psychology, Medical School Berlin, Berlin, Germany.

Objective: The current research comprehensively examined how grandiose and vulnerable narcissism are linked to intelligence and intelligence-related beliefs and emotions.

Method: In four studies (total N = 1,141), we tested the associations between both forms of narcissism, subjectively and objectively assessed intelligence, basic personality traits, test-related stress, beliefs about intelligence, and well-being.

Results: Both forms of narcissism (grandiose and vulnerable) were unrelated to objective intelligence. Grandiose narcissism was associated with high self-perceived intelligence (Studies 1-3) and explained more variance in self-perceived intelligence than objective intelligence and the Big Five personality traits. It was correlated with reduced distress in the context of IQ testing and low engagement in cognitive performance (Study 2). Individuals with high grandiose narcissism based their well-being (Study 3) partly on intelligence and considered intelligence important for success in different life domains, especially for social relations (Study 4). Vulnerable narcissism was unrelated to self-perceived intelligence (Studies 1-3) and went along with increased distress in the context of IQ testing (Study 2).

Conclusions: The results indicate that the topic of intelligence is of key importance for people with high grandiose narcissism psychological functioning and it also has some relevance for individuals with high vulnerable narcissism.
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http://dx.doi.org/10.1111/jopy.12520DOI Listing
August 2020

Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors.

J Med Chem 2018 09 23;61(17):7560-7572. Epub 2018 Aug 23.

The Norwegian Structural Biology Centre, Department of Chemistry , UiT The Arctic University of Norway , N-9037 Tromsø , Norway.

DYRK1A is one of five members of the dual-specificity tyrosine (Y) phosphorylation-regulated kinase (DYRK) family. The DYRK1A gene is located in the Down syndrome critical region and regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development. This has focused research on its role in neuronal degenerative diseases, including Alzheimer's and Down syndrome. Recent studies have also shown a possible role of DYRK1A in diabetes. Here we report a variety of scaffolds not generally known for DYRK1A inhibition, demonstrating their effects in in vitro assays and also in cell cultures. These inhibitors effectively block the tau phosphorylation that is a hallmark of Alzheimer's disease. The crystal structures of these inhibitors support the design of optimized and novel therapeutics.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01847DOI Listing
September 2018

Function of C-terminal peptides on enzymatic and interfacial adsorption properties of lipase from Gibberella zeae.

Biochim Biophys Acta Gen Subj 2018 12 17;1862(12):2623-2631. Epub 2018 Jul 17.

School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China. Electronic address:

Background: The crystal structure of lipase from Gibberella zeae (GZEL) indicates that its C-terminal extension is composed of a loop and a α-helix. This structure is unique, possibly providing novel evidence on lipase mechanisms.

Methods: Two C-terminally truncated mutants (GZEL-Δ(α-helix) and GZEL-Δ(α-helix+loop)) were constructed. The role of these secondary structure segments on enzymatic activities and interfacial binding properties of GZEL was investigated by using conventional pH-stat method and monomolecular film techniques. In addition, inactive variants (Ser144Ala) of wild-type GZEL and two truncated mutants were constructed and produced specifically for interfacial binding experiments.

Results: Compared to the wild-type GZEL, lipase and phospholipase activities were significantly decreased in the two mutants. Deletion of the α-helix had great influence on the lipase activity of GZEL, resulting in residual 7.3% activity; the additional deletion of the loop led to 8.1% lipase activity. As for the phospholipase function, residual activities of 63.0% and 35.4% were maintained for GZEL-Δ(α-helix) and GZEL-Δ(α-helix+loop), respectively. Findings obtained with monomolecular film experiments further indicated that the reduction in phospholipase activity occurred with the anionic phospholipid as substrate, but was not seen with zwitterionic phospholipid. Results of the maximum insertion pressure, synergy factor and binding kinetic parameters documented that the α-helix structure of GZEL strongly influence the binding and insertion of enzyme to the phospholipid monolayer. Moreover, the interfacial binding function of α-helix was partly conformed by connecting to the C-terminal of Aspergillus oryzae lipase.

General Significance: Our results provide important information on the understanding of the structure-function relationship of GZEL.
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http://dx.doi.org/10.1016/j.bbagen.2018.07.014DOI Listing
December 2018

The mental health continuum-short form: The structure and application for cross-cultural studies-A 38 nation study.

J Clin Psychol 2018 06 30;74(6):1034-1052. Epub 2018 Jan 30.

Nagoya University of Commerce and Business, Japan.

Objective: The Mental Health Continuum-Short Form (MHC-SF) is a brief scale measuring positive human functioning. The study aimed to examine the factor structure and to explore the cross-cultural utility of the MHC-SF using bifactor models and exploratory structural equation modelling.

Method: Using multigroup confirmatory analysis (MGCFA) we examined the measurement invariance of the MHC-SF in 38 countries (university students, N = 8,066; 61.73% women, mean age 21.55 years).

Results: MGCFA supported the cross-cultural replicability of a bifactor structure and a metric level of invariance between student samples. The average proportion of variance explained by the general factor was high (ECV = .66), suggesting that the three aspects of mental health (emotional, social, and psychological well-being) can be treated as a single dimension of well-being.

Conclusion: The metric level of invariance offers the possibility of comparing correlates and predictors of positive mental functioning across countries; however, the comparison of the levels of mental health across countries is not possible due to lack of scalar invariance. Our study has preliminary character and could serve as an initial assessment of the structure of the MHC-SF across different cultural settings. Further studies on general populations are required for extending our findings.
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http://dx.doi.org/10.1002/jclp.22570DOI Listing
June 2018

Single-cell analysis of the fate of c-kit-positive bone marrow cells.

NPJ Regen Med 2017 16;2:27. Epub 2017 Oct 16.

Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.

The plasticity of c-kit-positive bone marrow cells (c-kit-BMCs) in tissues different from their organ of origin remains unclear. We tested the hypothesis that c-kit-BMCs are functionally heterogeneous and only a subgroup of these cells possesses cardiomyogenic potential. Population-based assays fall short of identifying the properties of individual stem cells, imposing on us the introduction of single cell-based approaches to track the fate of c-kit-BMCs in the injured heart; they included viral gene-tagging, multicolor clonal-marking and transcriptional profiling. Based on these strategies, we report that single mouse c-kit-BMCs expand clonally within the infarcted myocardium and differentiate into specialized cardiac cells. Newly-formed cardiomyocytes, endothelial cells, fibroblasts and c-kit-BMCs showed in their genome common sites of viral integration, providing strong evidence in favor of the plasticity of a subset of BMCs expressing the c-kit receptor. Similarly, individual c-kit-BMCs, which were infected with multicolor reporters and injected in infarcted hearts, formed cardiomyocytes and vascular cells organized in clusters of similarly colored cells. The uniform distribution of fluorescent proteins in groups of specialized cells documented the polyclonal nature of myocardial regeneration. The transcriptional profile of myogenic c-kit-BMCs and whole c-kit-BMCs was defined by RNA sequencing. Genes relevant for engraftment, survival, migration, and differentiation were enriched in myogenic c-kit-BMCs, a cell subtype which could not be assigned to a specific hematopoietic lineage. Collectively, our findings demonstrate that the bone marrow comprises a category of cardiomyogenic, vasculogenic and/or fibrogenic c-kit-positive cells and a category of c-kit-positive cells that retains an undifferentiated state within the damaged heart.
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http://dx.doi.org/10.1038/s41536-017-0032-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678002PMC
October 2017

p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo.

EBioMedicine 2017 Feb 31;16:224-237. Epub 2017 Jan 31.

Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland. Electronic address:

p53 is an important modulator of stem cell fate, but its role in cardiac progenitor cells (CPCs) is unknown. Here, we tested the effects of a single extra-copy of p53 on the function of CPCs in the presence of oxidative stress mediated by doxorubicin in vitro and type-1 diabetes in vivo. CPCs were obtained from super-p53 transgenic mice (p53-tg), in which the additional allele is regulated in a manner similar to the endogenous protein. Old CPCs with increased p53 dosage showed a superior ability to sustain oxidative stress, repair DNA damage and restore cell division. With doxorubicin, a larger fraction of CPCs carrying an extra-copy of the p53 allele recruited γH2A.X reestablishing DNA integrity. Enhanced p53 expression resulted in a superior tolerance to oxidative stress in vivo by providing CPCs with defense mechanisms necessary to survive in the milieu of the diabetic heart; they engrafted in regions of tissue injury and in three days acquired the cardiomyocyte phenotype. The biological advantage provided by the increased dosage of p53 in CPCs suggests that this genetic strategy may be translated to humans to increase cellular engraftment and growth, critical determinants of successful cell therapy for the failing heart.
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http://dx.doi.org/10.1016/j.ebiom.2017.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474510PMC
February 2017

Do Narcissism and Emotional Intelligence Win Us Friends? Modeling Dynamics of Peer Popularity Using Inferential Network Analysis.

Pers Soc Psychol Bull 2016 Nov 28;42(11):1588-1599. Epub 2016 Sep 28.

4 Yale University, New Haven, CT, USA.

This research investigated effects of narcissism and emotional intelligence (EI) on popularity in social networks. In a longitudinal field study, we examined the dynamics of popularity in 15 peer groups in two waves ( N = 273). We measured narcissism, ability EI, and explicit and implicit self-esteem. In addition, we measured popularity at zero acquaintance and 3 months later. We analyzed the data using inferential network analysis (temporal exponential random graph modeling, TERGM) accounting for self-organizing network forces. People high in narcissism were popular, but increased less in popularity over time than people lower in narcissism. In contrast, emotionally intelligent people increased more in popularity over time than less emotionally intelligent people. The effects held when we controlled for explicit and implicit self-esteem. These results suggest that narcissism is rather disadvantageous and that EI is rather advantageous for long-term popularity.
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http://dx.doi.org/10.1177/0146167216666265DOI Listing
November 2016

The Dirty Dozen Scale: Validation of a Polish Version and Extension of the Nomological Net.

Front Psychol 2016 30;7:445. Epub 2016 Mar 30.

Faculty of Philosophy, Institute of Psychology, Jagiellonian University in Krakow Krakow, Poland.

In five studies (total N = 1300) we developed and validated a Polish version of the Dirty Dozen measure (DTDD-P) that measures the three traits of the Dark Triad, Machiavellianism, psychopathy, and narcissism. We detail the presence and stability of a bifactor structure of the 12 items and present evidence for good internal consistency and test-retest reliability. We examine the nomological network surrounding the Dark Triad and show that both the Dark Triad total score and the subscales have acceptable validity. We also present evidence on the Dark Triad and moral behavior. Dark Triad predicts utilitarian moral choice (e.g., approval for sacrificing somebody's life for the sake of saving others) and this link is mediated by low empathic concern. In total, our results suggest that the Polish Dirty Dozen-Parszywa Dwunastka-is valid, stable, and useful for the study of lingering puzzles in the literature.
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http://dx.doi.org/10.3389/fpsyg.2016.00445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811972PMC
April 2016

Individual differences in response to uncertainty and decision making: The role of behavioral inhibition system and need for closure.

Motiv Emot 2015;39(4):541-552

Institute of Psychology, Jagiellonian University, al. Mickiewicza 3, 31-120 Kraków, Poland.

In two studies, we examined the influence of behavioral inhibition system (BIS) and need for closure (NFC) on information processing in decision making. We expected that BIS would regulate behavior in a decisional context and that this relationship would be mediated by epistemic motivation expressed by NFC. In addition, drawing on contradictory findings in the literature on anxiety, NFC, and information processing, we investigated the moderating role of decision rules. The results supported our predictions. BIS was strongly and positively related to NFC, and through NFC it was related to decision-making style. Moreover, decision task characteristics moderated the relationship between NFC and decision making. When a task did not offer a confident decision rule, high NFC participants prolonged the information search more than low NFC individuals. However, when a reliable strategy was suggested, high NFC participants behaved in line with it. These results are discussed within an uncertainty management framework.
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http://dx.doi.org/10.1007/s11031-015-9478-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508368PMC
January 2015

Do I Mirror Your Mood if We're Peas in a Pod? Similarity and Liking in the Social Induction of Affect.

J Soc Psychol 2015 7;155(6):636-49. Epub 2015 May 7.

c Jagiellonian University in Krakow.

The present study investigates whether similarity in personality traits between a sender displaying affect and a receiver observing it influences the social induction of affect. We hypothesized that exposure to a similar sender would foster concordant affective reactions, whereas exposure to a dissimilar sender would foster discordant ones. To induce affect, we used short videos presenting a sender displaying happy versus sad emotional expressions. To manipulate personality similarity, we used a software program to generate brief bogus descriptions of the sender based on the receivers' prior responses to personality items. Our results demonstrated that dissimilarity led to decreased liking and, as a result, reduced the tendency to react with concordant affect to a happy sender's emotional expression. However, we found no evidence supporting the induction of discordant affective reactions.
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http://dx.doi.org/10.1080/00224545.2015.1047437DOI Listing
December 2016

Staphylococcal SplB serine protease utilizes a novel molecular mechanism of activation.

J Biol Chem 2014 May 8;289(22):15544-53. Epub 2014 Apr 8.

the Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30 387 Krakow, Poland, the Malopolska Centre of Biotechnology, 30 387 Krakow, Poland

Staphylococcal SplB protease belongs to the chymotrypsin family. Chymotrypsin zymogen is activated by proteolytic processing at the N terminus, resulting in significant structural rearrangement at the active site. Here, we demonstrate that the molecular mechanism of SplB protease activation differs significantly and we characterize the novel mechanism in detail. Using peptide and protein substrates we show that the native signal peptide, or any N-terminal extension, has an inhibitory effect on SplB. Only precise N-terminal processing releases the full proteolytic activity of the wild type analogously to chymotrypsin. However, comparison of the crystal structures of mature SplB and a zymogen mimic show no rearrangement at the active site whatsoever. Instead, only the formation of a unique hydrogen bond network, distant form the active site, by the new N-terminal glutamic acid of mature SplB is observed. The importance of this network and influence of particular hydrogen bond interactions at the N terminus on the catalytic process is demonstrated by evaluating the kinetics of a series of mutants. The results allow us to propose a consistent model where changes in the overall protein dynamics rather than structural rearrangement of the active site are involved in the activation process.
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http://dx.doi.org/10.1074/jbc.M113.507616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140910PMC
May 2014

c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy.

Circ Res 2014 Jan 29;114(1):41-55. Epub 2013 Oct 29.

From the Departments of Anesthesia (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.) and Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., E.I., M.A.P., P.G., J.K., T.H., M. Rota, P.A., A.L.), and Divisions of Cardiovascular Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.), Pulmonary and Critical Care Medicine (E.I., M.A.P., A.M.C.), and Newborn Medicine (M.A.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Rationale: Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell activation, but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown.

Objective: A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal.

Methods And Results: Here, we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot re-enter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy.

Conclusions: Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggest that a pool of functionally competent CSCs persists in the senescent heart and that this stem cell compartment can promote myocyte regeneration effectively, partly correcting the aging myopathy.
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http://dx.doi.org/10.1161/CIRCRESAHA.114.302500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959163PMC
January 2014

Structures of Drosophila cryptochrome and mouse cryptochrome1 provide insight into circadian function.

Cell 2013 Jun;153(6):1394-405

Department of Physiological Chemistry and Centre for Integrated Protein Science Munich (CIPSM), Butenandt Institute, Ludwig Maximilians University of Munich, Butenandtstrasse 5, 81377 Munich, Germany.

Drosophila cryptochrome (dCRY) is a FAD-dependent circadian photoreceptor, whereas mammalian cryptochromes (CRY1/2) are integral clock components that repress mCLOCK/mBMAL1-dependent transcription. We report crystal structures of full-length dCRY, a dCRY loop deletion construct, and the photolyase homology region of mouse CRY1 (mCRY1). Our dCRY structures depict Phe534 of the regulatory tail in the same location as the photolesion in DNA-repairing photolyases and reveal that the sulfur loop and tail residue Cys523 plays key roles in the dCRY photoreaction. Our mCRY1 structure visualizes previously characterized mutations, an NLS, and MAPK and AMPK phosphorylation sites. We show that the FAD and antenna chromophore-binding regions, a predicted coiled-coil helix, the C-terminal lid, and charged surfaces are involved in FAD-independent mPER2 and FBXL3 binding and mCLOCK/mBMAL1 transcriptional repression. The structure of a mammalian cryptochrome1 protein may catalyze the development of CRY chemical probes and the design of therapeutic metabolic modulators.
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http://dx.doi.org/10.1016/j.cell.2013.05.011DOI Listing
June 2013

Are narcissists sexy? Zeroing in on the effect of narcissism on short-term mate appeal.

Pers Soc Psychol Bull 2013 Jul 2;39(7):870-82. Epub 2013 Apr 2.

Department of Psychology, Humboldt-Universität zu Berlin, Unter den Linden 6, 10099 Berlin, Germany.

This research was aimed to provide a comprehensive test of the classic notion that narcissistic individuals are appealing as short-term romantic or sexual partners. In three studies, we tested the hypotheses that narcissism exerts a positive effect on an individual's mate appeal and that this effect is mediated by high physical attractiveness and high social boldness. We implemented a multimethod approach and used ratings of opposite sex persons (Study 1), ratings of friends (Study 2), and records of courtship outcomes in naturalistic interactions (Study 3) as indicators of mate appeal. In all cases, narcissism had a positive effect on mate appeal, which was mainly due to the agentic self-enhancement aspects of narcissism (rather than narcissists' lacking communion). As predicted, physical attractiveness and social boldness mediated the positive effect of narcissism on mate appeal. Findings further indicated that narcissism was more strongly linked to mate appeal than to friend appeal.
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http://dx.doi.org/10.1177/0146167213483580DOI Listing
July 2013

Quick and dirty: some psychosocial costs associated with the Dark Triad in three countries.

Evol Psychol 2013 Feb 15;11(1):172-85. Epub 2013 Feb 15.

School of Social Sciences and Psychology, University of Western Sydney, Bankstown, NSW, Australia.

The current study provides the first examination of the relationship between life history indicators and the Dark Triad traits in an international sample drawn from the U.S. (n = 264), Singapore (n = 185), and Poland (n = 177). In all three samples, the Dark Triad traits were associated with psychosocial costs, although there were more links in the Singaporean and Polish samples than in the American sample. In the U.S., the quality of one's romantic relationships and psychopathy were negatively correlated. Narcissism was higher in the Polish and American samples than in the Singaporean sample. Men scored higher than women did regardless of location and the sex difference in the individual differences in life histories was mediated by the Dark Triad composite. Results suggest the Dark Triad are related to a volatile socioecology composed of psychosocial costs in the familial, romantic, and platonic relationships.
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February 2013

Quantitative analyses of cryptochrome-mBMAL1 interactions: mechanistic insights into the transcriptional regulation of the mammalian circadian clock.

J Biol Chem 2011 Jun 25;286(25):22414-25. Epub 2011 Apr 25.

Max-Planck-Institute of Biochemistry, Department of Structural Cell Biology, Am Klopferspitz 18, 82152 Martinsried, Germany.

The mammalian cryptochromes mCRY1 and mCRY2 act as transcriptional repressors within the 24-h transcription-translational feedback loop of the circadian clock. The C-terminal tail and a preceding predicted coiled coil (CC) of the mCRYs as well as the C-terminal region of the transcription factor mBMAL1 are involved in transcriptional feedback repression. Here we show by fluorescence polarization and isothermal titration calorimetry that purified mCRY1/2CCtail proteins form stable heterodimeric complexes with two C-terminal mBMAL1 fragments. The longer mBMAL1 fragment (BMAL490) includes Lys-537, which is rhythmically acetylated by mCLOCK in vivo. mCRY1 (but not mCRY2) has a lower affinity to BMAL490 than to the shorter mBMAL1 fragment (BMAL577) and a K537Q mutant version of BMAL490. Using peptide scan analysis we identify two mBMAL1 binding epitopes within the coiled coil and tail regions of mCRY1/2 and document the importance of positively charged mCRY1 residues for mBMAL1 binding. A synthetic mCRY coiled coil peptide binds equally well to the short and to the long (wild-type and K537Q mutant) mBMAL1 fragments. In contrast, a peptide including the mCRY1 tail epitope shows a lower affinity to BMAL490 compared with BMAL577 and BMAL490(K537Q). We propose that Lys-537(mBMAL1) acetylation enhances mCRY1 binding by affecting electrostatic interactions predominantly with the mCRY1 tail. Our data reveal different molecular interactions of the mCRY1/2 tails with mBMAL1, which may contribute to the non-redundant clock functions of mCRY1 and mCRY2. Moreover, our study suggests the design of peptidic inhibitors targeting the interaction of the mCRY1 tail with mBMAL1.
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http://dx.doi.org/10.1074/jbc.M111.244749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121388PMC
June 2011

Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery.

Cell Cycle 2010 Mar 15;9(6):1104-11. Epub 2010 Mar 15.

Max-Planck-Institute of Biochemistry, Martinsried, Germany.

Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.
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http://dx.doi.org/10.4161/cc.9.6.10956DOI Listing
March 2010

Rapid and efficient hydrophilicity tuning of p53/mdm2 antagonists.

J Comb Chem 2009 Jul-Aug;11(4):631-9

Departments of Pharmaceutical Sciences and Chemistry, Drug Discovery Institute, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.

The protein-protein interaction of p53 and mdm2 is an important anticancer target. The interface, however, is very hydrophobic and naturally results in very hydrophobic antagonists. We used the Orru three component reaction (O-3CR) along with a rapid and efficient, recently discovered amidation reaction to dramatically improve the water solubility of our recently discovered low molecular weight p53/mdm2 antagonists. Arrays of amides were synthesized with improved hydrophilicity and retainment and/or improvement of p53/mdm2 inhibitory activity.
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http://dx.doi.org/10.1021/cc9000218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891308PMC
October 2010

High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx.

Cell Cycle 2009 Apr 16;8(8):1176-84. Epub 2009 Apr 16.

Max Planck Institute for Biochemistry, Martinsried, Germany.

The Mdm2 and Mdmx proteins are the principal negative regulators of the p53 tumor suppressor. Reactivation of p53 activity by disrupting the Mdm2/Mdmx-p53 interactions offers new possibilities for anticancer therapeutics. Here, we present crystal structures of two complexes, a p53-like mutant peptide with the N-terminal domains of Mdm2 and Mdmx, respectively. The structures reveal that the p53 mutant peptide (amino acid sequence: LTFEHYWAQLTS) assumes virtually identical conformations in both complexes despite the different shapes of the p53-binding pockets in these two proteins, has a more extended helical nature compared to the Mdm2-bound wild-type p53 peptide, and does not disturb the native folds of Mdm2 or Mdmx. The extension of the helical structure in the mutant p53 peptide greatly improves its binding to Mdm2 and Mdmx. The fluorescence polarization assay that we have developed using this peptide indicates the affinities towards Mdm2 of 3.6 nM and for Mdmx of 6.1 nM, compared to the low micromolar binding of a similar length wild-type p53 peptide to Mdm2/Mdmx. Our assay does not require expensive non-native amino acids, and allows measurements of the interaction with both Mdm2 and Mdmx in identical conditions-without modification of experimental conditions or setups between the two proteins. The structural information presented here, coupled with the robust fluorescence polarization assay, should enable development of a simple pharmacophore model of cross-selective Mdm2-Mdmx/p53 inhibitors.
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http://dx.doi.org/10.4161/cc.8.8.8185DOI Listing
April 2009

NMR screening for lead compounds using tryptophan-mutated proteins.

J Med Chem 2008 Aug 5;51(16):5035-42. Epub 2008 Aug 5.

Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.

NMR-based drug screening methods provide the most reliable characterization of binding propensities of ligands to their target proteins. They are, however, one of the least effective methods in terms of the amount of protein required and the time needed for acquiring an NMR experiment. We show here that the introduction of tryptophan to proteins permits rapid screening by monitoring a simple 1D proton NMR signal of the NH side chain ((N)H(epsilon)) of the tryptophan. The method could also provide quantitative characterization of the antagonist-protein and antagonist-protein-protein interactions in the form of KDs and fractions of the released proteins from their mutual binding. We illustrate the method with the lead compounds that block the Mdm2-p53 interaction and by studying inhibitors that bind to cyclin-dependent kinase 2 (CDK2).
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http://dx.doi.org/10.1021/jm8002813DOI Listing
August 2008

Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain.

Cell Cycle 2008 Aug 27;7(15):2441-3. Epub 2008 May 27.

The Mdmx oncoprotein has only recently emerged as a critical-independent to Mdm2-regulator of p53 activation. We have determined the crystal structure of the N-terminal domain of human Mdmx bound to a 15-residue transactivation domain peptide of human p53. The structure shows why antagonists of the Mdm2 binding to p53 are ineffective in the Mdmx-p53 interaction.
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http://dx.doi.org/10.4161/cc.6365DOI Listing
August 2008

Enzymatic activity of the Staphylococcus aureus SplB serine protease is induced by substrates containing the sequence Trp-Glu-Leu-Gln.

J Mol Biol 2008 May 3;379(2):343-56. Epub 2008 Apr 3.

Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.

Proteases are of significant importance for the virulence of Staphylococcus aureus. Nevertheless, their subset, the serine protease-like proteins, remains poorly characterized. Here presented is an investigation of SplB protease catalytic activity revealing that the enzyme possesses exquisite specificity and only cleaves efficiently after the sequence Trp-Glu-Leu-Gln. To understand the molecular basis for such selectivity, we solved the three-dimensional structure of SplB to 1.8 A. Modeling of substrate binding to the protease demonstrated that selectivity relies in part on a canonical specificity pockets-based mechanism. Significantly, the conformation of residues that ordinarily form the oxyanion hole, an essential structural element of the catalytic machinery of serine proteases, is not canonical in the SplB structure. We postulate that within SplB, the oxyanion hole is only formed upon docking of a substrate containing the consensus sequence motif. It is suggested that this unusual activation mechanism is used in parallel with classical determinants to further limit enzyme specificity. Finally, to guide future development, we attempt to point at likely physiological substrates and thus the role of SplB in staphylococcal physiology.
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http://dx.doi.org/10.1016/j.jmb.2008.03.059DOI Listing
May 2008

Isoquinolin-1-one inhibitors of the MDM2-p53 interaction.

ChemMedChem 2008 Jul;3(7):1118-28

Max Planck Institute for Biochemistry, 82152 Martinsried, Germany.

p53 has been at the centre of attention for drug design since the discovery of its growth-suppressive and pro-apoptotic activity. Herein we report the design and characterisation of a new class of isoquinolinone inhibitors of the MDM2-p53 interaction. Our identification of druglike and selective inhibitors of this protein-protein interaction included a straightforward in silico compound-selection process, a recently reported NMR spectroscopic approach for studying the MDM2-p53 interaction, and selectivity screening assays using cells with the same genetic background. The selected inhibitors were all able to induce apoptosis and the expression of p53-related genes, but only the isoquinolin-1-one-based inhibitors stabilised p53. Our NMR experiments give a persuading explanation for these results, showing that isoquinolin-1-one derivates are able to dissociate the preformed MDM2-p53 complex in vitro, releasing a folded and soluble p53. The joint application of these methods provides a framework for the discovery of protein interaction inhibitors as a promising starting point for further drug design.
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http://dx.doi.org/10.1002/cmdc.200800025DOI Listing
July 2008

Molecular basis for the inhibition of p53 by Mdmx.

Cell Cycle 2007 Oct 12;6(19):2386-92. Epub 2007 Oct 12.

Max Planck Institute for Biochemistry, Martinsried, Germany.

The oncoprotein Mdm2, and the recently intensely studied, homologues protein Mdmx, are principal negative regulators of the p53 tumor suppressor. The mechanisms by which they regulate the stability and activity of p53 are not fully established. We have determined the crystal structure of the N-terminal domain of Mdmx bound to a 15-residue p53 peptide. The structure reveals that although the principle features of the Mdm2-p53 interaction are preserved in the Mdmx-p53 complex, the Mdmx hydrophobic cleft on which the p53 peptide binds is significantly altered: a part of the cleft is blocked by sidechains of Met and Tyr of the p53-binding pocket of Mdmx. Thus specific inhibitors of Mdm2-p53 would not be optimal for binding to Mdmx. Our binding assays show indeed that nutlins, the newly discovered, potent antagonists of the Mdm2-p53 interaction, are not capable to efficiently disrupt the Mdmx-p53 interaction. To achieve full activation of p53 in tumor cells, compounds that are specific for Mdmx are necessary to complement the Mdm2 specific binders.
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http://dx.doi.org/10.4161/cc.6.19.4740DOI Listing
October 2007