Publications by authors named "Anna Zawadzka"

45 Publications

Efficacy and Safety of Hypofractionated Preoperative Radiotherapy for Primary Locally Advanced Soft Tissue Sarcomas of Limbs or Trunk Wall.

Cancers (Basel) 2021 Jun 14;13(12). Epub 2021 Jun 14.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Background: The use of adjuvant radiotherapy (RT) shows a significantly decreased incidence of local recurrence (LR) in soft tissue sarcomas (STS). This study aimed to assess the treatment scheme's effect in patients with primary STS treated at one institution.

Methods: In this phase 2 trial, 311 patients aged ≥18 years with primary, locally advanced STS of the extremity or trunk wall were assigned to multimodal therapy conducted at one institution. The preoperative RT scheme consisted of 5 Gy per fraction for a total dose of 25 Gy. Surgery was performed within 2-4 days from the last day of RT. The primary endpoint was LR-free survival (LRFS). Adverse events of the treatment were assessed.

Results: We included 311 patients with primary locally advanced STS. The median tumor size was 11 cm. In total, 258 patients (83%) had high-grade tumors. In 260 patients (83.6%), clear surgical margins (R0) were obtained. Ninety-six patients (30.8%) had at least one type of treatment adverse event. LR was observed in 13.8% patients. The 5-year overall survival was 63%.

Conclusion: In this group, with a significant percentage of patients with extensive, high-grade STS, hypofractionated preoperative RT was associated with good local control and tolerance.
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http://dx.doi.org/10.3390/cancers13122981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232096PMC
June 2021

"Clicking" fragment leads to novel dual-binding cholinesterase inhibitors.

Bioorg Med Chem 2021 Jul 7;42:116269. Epub 2021 Jun 7.

National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland; National Centre for Nuclear Research, 05-400 Otwock-Świerk, Poland.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using "clickable" fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.
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http://dx.doi.org/10.1016/j.bmc.2021.116269DOI Listing
July 2021

Optical and morphological properties of Curcuma longa dye for dye-sensitized solar cells.

Environ Sci Pollut Res Int 2021 Jun 7. Epub 2021 Jun 7.

Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Wilenska 4, 87-100, Torun, Poland.

New experimental results of morphological and optical properties of Curcuma longa dye thin film were investigated. The thin films were deposited by physical vapor deposition technique. Morphological properties were measured using atomic force microscopy technique and they show a granular structure which above there are nanotubes shapes. Photoluminescence of Curcuma longa at low temperature was investigated and discussed for the first time. The temperature effect from 77 to 300 K of Curcuma longa thin film has been shown and luminescence was strongly observed. Photoelectrochemical parameters of the dye-sensitized solar cell based on Curcuma longa have been computed via the finite element method. The power conversion efficiency is about 0.86% obtained from short circuit current, open-circuit voltage, and fill factor of 0.13 mA/cm, 0.52 mV, and 0.83, respectively. As a result, Curcuma longa dye can be applied to dye-sensitized solar cells.
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http://dx.doi.org/10.1007/s11356-021-14551-9DOI Listing
June 2021

Effects and Safety of Convalescent Plasma Administration in a Group of Polish Pediatric Patients with COVID-19: A Case Series.

Life (Basel) 2021 Mar 17;11(3). Epub 2021 Mar 17.

Department of Infectious Diseases and Child Neurology, Poznan University of Medical Sciences, Szpitalna Street 27/33, 60-572 Poznań, Greater Poland Voivodeship, Poland.

Despite the enormous advances in knowledge about the SARS-CoV-2 infection, the optimal treatment for COVID-19 is still not well defined. The use of convalescent plasma seems to be a promising method of treatment but requires further evaluation. Although it is usually mild, in children with underlying chronic diseases, the course of SARS-CoV-2 infection may be very severe. We described a series of 13 pediatric patients (mean age 10.4 years, median 12) treated with convalescent plasma as a method of COVID-19 therapy. Medical history, with particular emphasis on comorbidities, clinical course, laboratory parameters, supportive treatment and virus elimination time, were analyzed. The mean hospitalization time was 22.6 days (median 20). The most common abnormalities included increased levels of C-reactive protein, D-dimer, and lymphopenia. Median time from symptom onset to convalescent plasma transfusion was 10.6 days (median 7 days). Six patients (46.2%) had a viral clearance on RT-PCR method from a nasopharyngeal swab within 3 days of transfusion, while in the remaining patients the mean elimination time was 12.1 days (median 6 days). Clinical improvement was achieved in all patients; no adverse effects were found in any of the cases. Convalescent plasma may be a promising treatment for COVID-19 in children.
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http://dx.doi.org/10.3390/life11030247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002380PMC
March 2021

The effects of viewing a winter forest landscape with the ground and trees covered in snow on the psychological relaxation of young Finnish adults: A pilot study.

PLoS One 2021 7;16(1):e0244799. Epub 2021 Jan 7.

Department of General Pedagogy, Faculty of Social Science, Olsztyn, Poland.

Forest bathing is an outdoor activity, and it might be a promising preventive treatment for social problems involving stress. A vast number of studies confirm the positive effects of this activity on people's health. Nevertheless, little is known about the influence of winter forest bathing when conducted in an environment with snow cover on the ground and trees. Thus, a crossover experiment was designed in this study, with the participation of twenty-two healthy university students from Finland. During the experiment, a short exposition by a forest environment or landscape with buildings (as a control) was applied. Participants self-reported their psychological relaxation before and after the exposition, and the results were analyzed and compared. The mood, emotions, restorativeness, and subjective vitality were recorded as indices reflecting the psychological relaxation effect. The negative mood indices decreased significantly after exposition by the snow-covered environment, but the positive 'vigor' indices did not increase or decrease significantly. The level of negative emotions increased after the exposition with the control environment. Likewise, positive emotions decreased after the interaction with the control. Restorativeness was significantly increased after the exposition by the experimental forest but decreased after the viewing of the control buildings. The size of the effect in terms of restorativeness was the highest in this experiment. The subjective vitality was lowered as affected by the control, but it did not increase or decrease after the exposition with the experimental forest. There is probably an effect from the slight interruption in the process from the influence of the forest greens on participants because their vigor and vitality did not increase after the exposition with this environment in the study. However, snow might influence the participants as a calming and emotion-lowering component of the environment, but this idea needs to be further explored with the involvement of participants from other countries who would be viewing forest environments with snow cover and whose psychological relaxation could be measured.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244799PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790245PMC
May 2021

Effect of Ar Gas Pressure on LSPR Property of Au Nanoparticles: Comparison of Experimental and Theoretical Studies.

Nanomaterials (Basel) 2020 May 31;10(6). Epub 2020 May 31.

University of Angers, MOLTECH Anjou, CNRS UMR 6200, 2 Bd Lavoisier, F-49045 Angers, France.

In this study, the thin films were produced by using pulsed laser deposition (PLD) technique from gold (Au) nanoparticles deposited on two kinds of substrates under different argon (Ar) gas pressure. Microscope glass slides and silicon (100) wafers were used as amorphous and crystal substrates. The films were deposited under 2 × 10 mbar, 1 × 10 mbar, 2 × 10 mbar argon (Ar) ambient gas pressure. Effect of the background gas pressure on the plasma plume of the ablated Au nanoparticles was investigated in details. Morphology of Au nanoparticle thin films was investigated by means of atomic force microscopy (AFM) technique. Absorption spectra of Au nanoparticles were examined by using UV-Vis spectrometry. Extinction spectra of Au nanoparticles were calculated by using metallic nano particles boundary element method (MNPBEM) simulation programme. Both experimental spectra and simulation data for Au nanoparticles were obtained and compared in this work. It was concluded that they are also in good agreement with literature data. The measurements and the simulation results showed that localized surface plasmon resonance (LSPR) peaks for Au nanoparticles were located in the near infrared region (NIR) because of the larger size of the disk-like shape of Au nanoparticles, and the near-field coupling between Au nanoparticles. It was demonstrated that as the ambient gas (Ar) pressure was increased, the size and the density of Au nanoparticles on the substrate were decreased and the LSPR peak shifts toward the short wavelength region in the spectrum. This shift has been explained by the changes in the morphology of produced thin films.
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http://dx.doi.org/10.3390/nano10061071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352769PMC
May 2020

SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells.

Cell Rep 2019 09;28(13):3329-3337.e5

Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address:

Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence. We validated the expression of some of these SASP factors in cultured cells and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, selective removal of senescent cells using transgenic p16-3MR mice showed that clearing senescent cells attenuates the increased clotting caused by doxorubicin. Our study provides an in-depth, unbiased analysis of the SASP and unveils a function for cellular senescence in hemostasis.
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http://dx.doi.org/10.1016/j.celrep.2019.08.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907691PMC
September 2019

A systematic review and meta-analysis of pT2 rectal cancer spread and recurrence pattern: Implications for target design in radiation therapy for organ preservation.

Radiother Oncol 2019 04 14;133:20-27. Epub 2019 Jan 14.

Department of Radiotherapy I, Maria Skłodowska-Curie Memorial Cancer Centre, Warsaw, Poland.

Background: There are no guidelines on clinical target volume (CTV) delineation for cT2 rectal cancer treated with organ preservation.

Materials And Methods: A systematic review and meta-analysis were performed to determine the extent of distal mesorectal (DMS) and distal intramural spread (DIS), the risk of lateral lymph node (LLN) metastases in pT2 tumours, and regional recurrence pattern after organ preservation.

Results: The rate of DMS > 1 cm was 1.9% (95% CI: 0.4-5.4%), maximum extent: 1.3 cm. The rate of DIS > 0.5 cm was 4.7% (95% CI: 1.3-11.5%), maximum extent: 0.8 cm. The rate of LLN metastases was 8.2% (95% CI: 6.7-9.9%) for tumours below or at peritoneal reflexion and 0% for higher tumours. Regional nodal recurrences alone were recorded in 1.0% (95% CI: 0.5-1.7%) of patients after watch-and-wait and in 2.1% (95% CI: 1.2-3.4%) after preoperative radiotherapy and local excision. Thus, the following rules for CTV delineation are proposed: caudal border 1.5 cm from the tumour to account for DMS or 1 cm to account for DIS, whichever is more caudal; cranial border at S2/S3 interspace; inclusion of LLN for tumours at or below peritoneal reflexion. A planning study was performed in eight patients to compare dose-volume parameters obtained using these rules to that obtained using current guidelines for advanced cancers. The proposed rules led to a mean 18% relative reduction of planning target volume, which resulted in better sparing of organs-at-risk.

Conclusion: This meta-analysis suggests a smaller CTV for cT2 tumours than the current guidelines designed for advanced cancers.
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http://dx.doi.org/10.1016/j.radonc.2018.12.024DOI Listing
April 2019

Selected Organometallic Compounds for Third Order Nonlinear Optical Application.

Nanomaterials (Basel) 2019 Feb 13;9(2). Epub 2019 Feb 13.

Laboratoire MOLTECH-Anjou, Université d'Angers, CNRS UMR 6200, 2 Boulevard Lavoisier, 49045 Angers, France.

In this paper, we present the third harmonic generation response of Znq₂ (Bis-(8-hydroxyquinolinato)zinc), Cuq₂ (8-Hydroxyquinoline copper(II)), and Alq₃ (Tris-(8-hydroxyquinoline)aluminum) organometallic compounds. An experiment was conducted for s and p polarizations of incident beam, using the Maker fringes technique. The third order nonlinear susceptibility χ was estimated using the Kubodera and Kobayashi comparative model, on the grounds that presented compounds exhibit high linear absorption of the generated third harmonic wavelength (355 nm). These complexes were deposited as thin films using the physical vapor deposition (PVD) method. Investigated complexes vary in terms of the coordination center and number of quinoline ligands, which visibly influence their nonlinear response. The global hybrid B3LYP functional with the basis set 6-31G(d) was used in computing the linear and non-linear optical properties. The computed γ value (8765.36 × 10 esu for Cuq₂) is superior to that of methylene blue (γ = 32.00 × 10 esu). The calculated theoretical values were found to be in good agreement with the experimental results.
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http://dx.doi.org/10.3390/nano9020254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409707PMC
February 2019

Water Nanodroplet on a Hydrocarbon "Carpet"-The Mechanism of Water Contact Angle Stabilization by Airborne Contaminations on Graphene, Au, and PTFE Surfaces.

Langmuir 2019 01 2;35(2):420-427. Epub 2019 Jan 2.

Faculty of Chemistry, Physicochemistry of Carbon Materials Research Group , Nicolaus Copernicus University in Toruń , Gagarin Street 7 , 87-100 Toruń , Poland.

Wetting is very common phenomenon, and it is well documented that the wettability of a solid depends on the surface density of adsorbed airborne hydrocarbons. This "hydrocarbon hypothesis" has been experimentally confirmed for different surfaces, for example, graphene, TiO, and SiO; however, there are no scientific reports describing the influence of airborne contaminants on the water contact angle (WCA) value measured on the polytetrafluoroethylene (PTFE) surface. Using experimental data showing the influence of airborne hydrocarbons on the wettability of graphene, gold and PTFE by water, together with Molecular Dynamics simulation results we prove that the relation between the WCA and the surface concentration of hydrocarbons ( n-decane, n-tridecane, and n-tetracosane) is more complex than has been assumed up until now. We show, in contrast to commonly approved opinion, that adsorbed hydrocarbons can increase (graphene, Au) or decrease (PTFE) the WCA of a nanodroplet sitting on a surface. Using classical thermodynamics, a simple theoretical approach is developed. It is based on two adsorbed hydrocarbon states, namely, "carpet" and "dimple". In the "carpet" state a uniform layer of alkane molecules covers the entire substrate. In contrast, in the "dimple" state, the preadsorbed layer of alkane molecules covers only the open surface. Simple thermodynamic balance between the two states explains observed experimental and simulation results, forming a good starting point for future studies.
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http://dx.doi.org/10.1021/acs.langmuir.8b03790DOI Listing
January 2019

The role of the gynaecologist in the promotion and maintenance of oral health during pregnancy.

Ginekol Pol 2018 ;89(3):120-124

Department of Paediatric Dentistry, Medical University of Warsaw, Poland.

Objectives: The aim of the study was to assess routine dental examination attendance of pregnant women and a possible impact of gynaecological referrals on the attendance rate.

Material And Methods: An electronic survey was conducted that was inclusive of women up to 5 years following delivery. The questions related to socio-demographic data, the course of pregnancy and childbirth, and visits to dental office during pregnancy. For statistical analysis, the authors utilized the chi-square test, Spearman's rank correlation coefficient and odds ratios. A significance level of 0.05 has been assumed.

Results: A total of 3455 questionnaires were analyzed encompassing women aged 13.1-45.4 years. The respondents were on average 1.78 ± 1.44 years after childbirth. The population comprises of women in 59.1% from large cities, in 74.8% with higher education and in 41% with good socio-economic status. A total of 62.3% of women from the study population have visited a dentist for a routine dental examination. Gynaecologists have given a simple referral to a dentist to 17.6% of all women. 45.9% of them were further requested to provide back the feedback of their dental consultation. Dental appoint-ments were upheld by 87.3% of referred women and by 56.9% of those without a referral (OR = 5.20 (4.05-6.67); p < 0.001). Among those who were referred, dental appointments were upheld in 91.7% of cases when further asked to provide oral health feedback and in 83.5% of cases in absence of such further request (OR = 2.19 (1.3-3.66); p = 0.003).

Conclusions: It was determined that referrals from a gynaecologist, and associated oral health feedback requests increase the frequency of abiding to dental appointments during pregnancy. As such, it is necessary to increase the involvement of gynaecologists in the promotion and maintenance of perinatal oral health.
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http://dx.doi.org/10.5603/GP.a2018.0021DOI Listing
July 2018

Simultaneous induction and blockade of autophagy by a single agent.

Cell Death Dis 2018 03 2;9(3):353. Epub 2018 Mar 2.

Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warsaw, Poland.

Besides cell death, autophagy and cell senescence are the main outcomes of anticancer treatment. We demonstrate that tacrine-melatonin heterodimer C10, a potent anti-Alzheimer's disease drug, has an antiproliferative effect on MCF-7 breast cancer cells. The main cell response to a 24 h-treatment with C10 was autophagy enhancement accompanied by inhibition of mTOR and AKT pathways. Significantly increased autophagy markers, such as LC3B- and ATG16L-positive vesicles, confirmed autophagy induction by C10. However, analysis of autophagic flux using mCherry-GFP-LC3B construct revealed inhibition of autophagy by C10 at the late-stage. Moreover, electron microscopy and analysis of colocalization of LC3B and LAMP-1 proteins provided evidence of autophagosome-lysosome fusion with concomitant inhibition of autolysosomal degradation function. After transient treatment with IC dose of C10 followed by cell culture without the drug, 20% of MCF-7 cells displayed markers of senescence. On the other hand, permanent cell treatment with C10 resulted in massive cell death on the 5th or 6th day. Recently, an approach whereby autophagy is induced by one compound and simultaneously blocked by the use of another one has been proposed as a novel anticancer strategy. We demonstrate that the same effect may be achieved using a single agent, C10. Our findings offer a new, promising strategy for anticancer treatment.
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http://dx.doi.org/10.1038/s41419-018-0383-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834631PMC
March 2018

Method of predicting the mean lung dose based on a patient׳s anatomy and dose-volume histograms.

Med Dosim 2017 Spring;42(1):57-62

Medical Physics Department, Centre of Oncology, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.

The aim of this study was to propose a method to predict the minimum achievable mean lung dose (MLD) and corresponding dosimetric parameters for organs-at-risk (OAR) based on individual patient anatomy. For each patient, the dose for 36 equidistant individual multileaf collimator shaped fields in the treatment planning system (TPS) was calculated. Based on these dose matrices, the MLD for each patient was predicted by the homemade DosePredictor software in which the solution of linear equations was implemented. The software prediction results were validated based on 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) plans previously prepared for 16 patients with stage III non-small-cell lung cancer (NSCLC). For each patient, dosimetric parameters derived from plans and the results calculated by DosePredictor were compared. The MLD, the maximum dose to the spinal cord (D) and the mean esophageal dose (MED) were analyzed. There was a strong correlation between the MLD calculated by the DosePredictor and those obtained in treatment plans regardless of the technique used. The correlation coefficient was 0.96 for both 3D-CRT and VMAT techniques. In a similar manner, MED correlations of 0.98 and 0.96 were obtained for 3D-CRT and VMAT plans, respectively. The maximum dose to the spinal cord was not predicted very well. The correlation coefficient was 0.30 and 0.61 for 3D-CRT and VMAT, respectively. The presented method allows us to predict the minimum MLD and corresponding dosimetric parameters to OARs without the necessity of plan preparation. The method can serve as a guide during the treatment planning process, for example, as initial constraints in VMAT optimization. It allows the probability of lung pneumonitis to be predicted.
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http://dx.doi.org/10.1016/j.meddos.2016.12.001DOI Listing
September 2017

Molecular cloning of melatonin 3-hydroxylase and its production of cyclic 3-hydroxymelatonin in rice (Oryza sativa).

J Pineal Res 2016 Nov 31;61(4):470-478. Epub 2016 Aug 31.

Department of Biotechnology, Bioenergy Research Center, Chonnam National University, Gwangju, South Korea.

Melatonin is metabolized in animals to cyclic 3-hydroxymelatonin (3-OHM) not by an enzymatic pathway, but by interaction with hydroxyl radicals. The production of 3-OHM in animals suggests the possible presence of 3-OHM in plants. Prior to the identification of 3-OHM in plants, we directly cloned the corresponding gene(s) responsible for 3-OHM synthesis using Escherichia coli library strains expressing genes belonging to the 2-oxoglutarate-dependent dioxygenase (2-ODD) superfamily from rice. Three of 35 E. coli library strains supplemented with 1 mmol/L melatonin were found to produce 3-OHM in their extracellular medium, suggestive of three 2-ODD genes involved in 3-OHM production. The purified recombinant 2-ODD 11, 2-ODD 26, and 2-ODD 33 proteins were shown to catalyze the metabolism of melatonin to 3-OHM, with 2-ODD 11 showing the highest melatonin 3-hydroxylase (M3H) catalytic activity. Consistent with the presence of M3H genes, rice leaves supplemented with 5 mmol/L melatonin produced 3-OHM [233 μg/g fresh weight (FW)], 2-hydroxymelatonin (21 μg/g FW), and N -acetyl-N -formyl-5-methoxykynuramine (5 μg/g FW). Three M3H transcripts were induced upon the treatment of rice leaves with cadmium followed by an increase in M3H enzyme activity. Cloning of M3H genes in plants has paved the way for the studies of melatonin in plants in terms of its multiple physiological roles.
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http://dx.doi.org/10.1111/jpi.12361DOI Listing
November 2016

The Effects of the Activation of Money and Credit Card vs. that of Activation of Spirituality - Which One Prompts Pro-Social Behaviours?

Curr Psychol 2016;35(3):344-353. Epub 2014 Dec 24.

Psychology Institute of Psychology, University of Gdansk, ul. Bażyńskiego 4, 80-592 Gdańsk, Poland.

Pro-social behaviours may be prompted or inhibited depending on the situation. Numerous experiments show that, when exposed to the idea of money, people are less willing to help, devote their time or share their resources with others (Vohs et al. Science, 314, 1154-1156, 2006, Current Directions in Psychological Science, 17(3), 208-212, 2008). Conversely, when exposed to the idea of spirituality, they often cheat less and are more willing to help others (Mazar and Ariely Journal of Marketing Research, 45, 633-644, 2008; Randolph-Seng and Nielsen The International Journal for the Psychology of Religion, 17(4), 303-315, 2007). The aim of this article is to present the results of two experiments in which we activated thoughts about money, i.e. both cash and credit cards, and thoughts about spirituality in order to find out in what way these two kinds of activation may influence pro-social behaviours. In experiment 1, participants, when reminded of money, offered lower donations to others whereas those reminded of spirituality offered higher donations. In experiment 2, those participants reminded of money offered to devote less time to help others whereas those reminded of spirituality offered to devote more time to help others.
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http://dx.doi.org/10.1007/s12144-014-9299-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031715PMC
December 2014

Variation and quantification among a target set of phosphopeptides in human plasma by multiple reaction monitoring and SWATH-MS2 data-independent acquisition.

Electrophoresis 2014 Dec 10;35(24):3487-97. Epub 2014 Jul 10.

Buck Institute for Research on Aging, Novato, CA, USA.

Human plasma contains proteins that reflect overall health and represents a rich source of proteins for identifying and understanding disease pathophysiology. However, few studies have investigated changes in plasma phosphoproteins. In addition, little is known about the normal variations in these phosphoproteins, especially with respect to specific sites of modification. To address these questions, we evaluated variability in plasma protein phosphorylation in healthy individuals using multiple reaction monitoring (MRM) and SWATH-MS2 data-independent acquisition. First, we developed a discovery workflow for phosphopeptide enrichment from plasma and identified targets for MRM assays. Next, we analyzed plasma from healthy donors using an analytical workflow consisting of MRM and SWATH-MS2 that targeted phosphopeptides from 58 and 68 phosphoproteins, respectively. These two methods produced similar results showing low variability in 13 phosphosites from 10 phosphoproteins (CVinter < 30%) and high interpersonal variation of 16 phosphosites from 14 phosphoproteins (CVinter > 30%). Moreover, these phosphopeptides originate from phosphoproteins involved in cellular processes governing homeostasis, immune response, cell-extracellular matrix interactions, lipid and sugar metabolism, and cell signaling. This limited assessment of technical and biological variability in phosphopeptides generated from plasma phosphoproteins among healthy volunteers constitutes a reference for future studies that target protein phosphorylation as biomarkers.
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http://dx.doi.org/10.1002/elps.201400167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565165PMC
December 2014

Phosphoprotein secretome of tumor cells as a source of candidates for breast cancer biomarkers in plasma.

Mol Cell Proteomics 2014 Apr 6;13(4):1034-49. Epub 2014 Feb 6.

Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, California 94945;

Breast cancer is a heterogeneous disease whose molecular diversity is not well reflected in clinical and pathological markers used for prognosis and treatment selection. As tumor cells secrete proteins into the extracellular environment, some of these proteins reach circulation and could become suitable biomarkers for improving diagnosis or monitoring response to treatment. As many signaling pathways and interaction networks are altered in cancerous tissues by protein phosphorylation, changes in the secretory phosphoproteome of cancer tissues could reflect both disease progression and subtype. To test this hypothesis, we compared the phosphopeptide-enriched fractions obtained from proteins secreted into conditioned media (CM) derived from five luminal and five basal type breast cancer cell lines using label-free quantitative mass spectrometry. Altogether over 5000 phosphosites derived from 1756 phosphoproteins were identified, several of which have the potential to qualify as phosphopeptide plasma biomarker candidates for the more aggressive basal and also the luminal-type breast cancers. The analysis of phosphopeptides from breast cancer patient plasma and controls allowed us to construct a discovery list of phosphosites under rigorous collection conditions, and second to qualify discovery candidates generated from the CM studies. Indeed, a set of basal-specific phosphorylation CM site candidates derived from IBP3, CD44, OPN, FSTL3, LAMB1, and STC2, and luminal-specific candidates derived from CYTC and IBP5 were selected and, based on their presence in plasma, quantified across all cell line CM samples using Skyline MS1 intensity data. Together, this approach allowed us to assemble a set of novel cancer subtype specific phosphopeptide candidates for subsequent biomarker verification and clinical validation.
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http://dx.doi.org/10.1074/mcp.M113.035485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977182PMC
April 2014

Highly selective inhibition of butyrylcholinesterase by a novel melatonin-tacrine heterodimers.

J Pineal Res 2013 May;54(4):435-41

Faculty of Chemistry, University of Warsaw, Warsaw, Poland.

Novel inhibitors of cholinesterases, especially butyrylcholinesterase (BuChE), were obtained by coupling melatonin-tacrine heterodimers via the carbamate bond. Compounds 14a-i possessed potent cholinesterase inhibitory activity (with IC50 values as low as 1.18 nM for acetylcholinesterase (AChE) and 0.24 nM for butyrylcholinesterase (BuChE)). These heterodimers exhibit selectivity toward BuChE, being from 4- to 256-fold more active toward BuChE than AChE, but still acting as better AChE inhibitors than tacrine 4.
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http://dx.doi.org/10.1111/jpi.12006DOI Listing
May 2013

Target volume for postoperative radiotherapy in non-small cell lung cancer: results from a prospective trial.

Radiother Oncol 2013 Jul 18;108(1):61-5. Epub 2013 Jun 18.

Department of Radiotherapy, The Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.

Background And Purpose: A previous prospective trial reported that three-dimensional conformal postoperative radiotherapy (PORT) for pN2 NSCLC patients using a limited clinical target volume (CTV) had a late morbidity rate and pulmonary function that did not differ from those observed in pN1 patients treated with surgery without PORT. The aim of this study was to assess locoregional control and localization of failure in patients treated with PORT.

Materials And Methods: The pattern of locoregional failure was evaluated retrospectively in 151 of 171 patients included in the PORT arm. The CTV included the involved lymph node stations and those with a risk of invasion >10%. Competing risk analysis was used to assess the incidence of locoregional failure and its location outside the CTV.

Results: Overall survival at 5years was 27.1% with a median follow-up of 67months for 40 living patients. The 5-year cumulative incidence of locoregional failure was 19.4% (95% CI: 18.2-20.5%) including a failure rate of 2% (95% CI: 0-17%) in locations outside or at the border of the CTV.

Conclusions: The use of limited CTV was associated with acceptable risk of geographic miss. Overall locoregional control was similar to that reported by other studies using PORT for pN2 patients.
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http://dx.doi.org/10.1016/j.radonc.2013.05.023DOI Listing
July 2013

Synthesis, antidepressant evaluation and docking studies of long-chain alkylnitroquipazines as serotonin transporter inhibitors.

Chem Biol Drug Des 2013 Jun 11;81(6):695-706. Epub 2013 Apr 11.

Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway.

Twelve alkyl analogues (1-12) of the high-affinity serotonin transporter (SERT) inhibitor 6-nitroquipazine (6-NQ) were synthesized and studied using in vitro radioligand competition binding assays to determine their binding affinity (Ki ). The putative antidepressant activity of five of the binders with the highest SERT binding affinities was studied by the forced swim and locomotor activity mouse tests. The three-dimensional (3D) structures of 8 and 9 were determined using NOE NMR technique. Flexible docking of the compounds was undertaken to illustrate the binding of the compounds in the SERT model. Our results showed that several of the 6-NQ analogues are high-affinity SERT inhibitors and indicated that the octyl (8), decyl (10) and dodecyl (12) 6-NQ analogues exhibit moderate antidepressant activity.
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http://dx.doi.org/10.1111/cbdd.12116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665732PMC
June 2013

3-(2-Acetamido-eth-yl)-1H-indol-5-yl 4-nitro-phenyl carbonate.

Acta Crystallogr Sect E Struct Rep Online 2012 Oct 12;68(Pt 10):o2915. Epub 2012 Sep 12.

National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland ; NationalCentre for Nuclear Research, 05-400 Otwock-Świerk, Poland.

In the title mol-ecule, C(19)H(17)N(3)O(6), the indole ring system is essentially planar (r.m.s. deviation = 0.009 Å) and forms a dihedral angle of 31.96 (9)° with the nitro-substituted benzene ring. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers which are connected by further N-H⋯O hydrogen bonds into a two-dimensional network parallel to (102).
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http://dx.doi.org/10.1107/S1600536812038238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470262PMC
October 2012

NMR findings in patients after wrist trauma with a negative plain radiographs.

Pol J Radiol 2012 Apr;77(2):7-13

Department of Neonatal and Genitourinary Radiology of the Medical University of Gdańsk, Gdańsk, Poland.

Background: The purpose was to assess the prevalence and location of the injuries of the carpal bones and soft tissue of the wrist on NMR in patients with negative radiographs.

Material/methods: A total of 89 patients (9-81years) were consecutively examined after wrist trauma. Radiograms were performed in four projections: AP, PA, oblique and lateral. In 63 cases of negative radiographs and persistent clinical problem, simplified NMR (T1,T2, STIR; in coronal plane) was conducted with a 1.5 Tesla magnet. Results were evaluated by two independent observers. A positive X-ray result was stated when at least one observer suggested bone fracture. The MR images were viewed for detection of possible bone fracture, bone edema and soft tissue injuries. Cohen's kappa coefficient was calculated to assess the quality of chosen criteria by means of agreement between both observers and both methods.

Results: As many as 26 X-ray studies were classified as positive. Substantial agreement between independent observers was found (kappa=0.63). In 17 cases out of 63 with two negative wrist radiogram, the NMR result was positive (19%). The most frequently fractured or injured bone was scaphoid (10 cases) and distal radius (5 cases). Fair agreement was found between X-ray and NMR studies (kappa=0.37) due to different diagnostic information received in both methods.

Conclusions: Simplified NMR imaging of the wrist proved to be strongly efficient in the detection of pathological changes in injured wrists.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403806PMC
http://dx.doi.org/10.12659/pjr.882964DOI Listing
April 2012

Platform-independent and label-free quantitation of proteomic data using MS1 extracted ion chromatograms in skyline: application to protein acetylation and phosphorylation.

Mol Cell Proteomics 2012 May 26;11(5):202-14. Epub 2012 Mar 26.

Buck Institute for Research on Aging, Novato, California 94945, USA.

Despite advances in metabolic and postmetabolic labeling methods for quantitative proteomics, there remains a need for improved label-free approaches. This need is particularly pressing for workflows that incorporate affinity enrichment at the peptide level, where isobaric chemical labels such as isobaric tags for relative and absolute quantitation and tandem mass tags may prove problematic or where stable isotope labeling with amino acids in cell culture labeling cannot be readily applied. Skyline is a freely available, open source software tool for quantitative data processing and proteomic analysis. We expanded the capabilities of Skyline to process ion intensity chromatograms of peptide analytes from full scan mass spectral data (MS1) acquired during HPLC MS/MS proteomic experiments. Moreover, unlike existing programs, Skyline MS1 filtering can be used with mass spectrometers from four major vendors, which allows results to be compared directly across laboratories. The new quantitative and graphical tools now available in Skyline specifically support interrogation of multiple acquisitions for MS1 filtering, including visual inspection of peak picking and both automated and manual integration, key features often lacking in existing software. In addition, Skyline MS1 filtering displays retention time indicators from underlying MS/MS data contained within the spectral library to ensure proper peak selection. The modular structure of Skyline also provides well defined, customizable data reports and thus allows users to directly connect to existing statistical programs for post hoc data analysis. To demonstrate the utility of the MS1 filtering approach, we have carried out experiments on several MS platforms and have specifically examined the performance of this method to quantify two important post-translational modifications: acetylation and phosphorylation, in peptide-centric affinity workflows of increasing complexity using mouse and human models.
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http://dx.doi.org/10.1074/mcp.M112.017707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418851PMC
May 2012

Lectin chromatography/mass spectrometry discovery workflow identifies putative biomarkers of aggressive breast cancers.

J Proteome Res 2012 Apr 13;11(4):2508-20. Epub 2012 Mar 13.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, 513 Parnassus Avenue, Box 0665, San Francisco, California 94143, United States.

We used a lectin chromatography/MS-based approach to screen conditioned medium from a panel of luminal (less aggressive) and triple negative (more aggressive) breast cancer cell lines (n=5/subtype). The samples were fractionated using the lectins Aleuria aurantia (AAL) and Sambucus nigra agglutinin (SNA), which recognize fucose and sialic acid, respectively. The bound fractions were enzymatically N-deglycosylated and analyzed by LC-MS/MS. In total, we identified 533 glycoproteins, ∼90% of which were components of the cell surface or extracellular matrix. We observed 1011 glycosites, 100 of which were solely detected in ≥3 triple negative lines. Statistical analyses suggested that a number of these glycosites were triple negative-specific and thus potential biomarkers for this tumor subtype. An analysis of RNaseq data revealed that approximately half of the mRNAs encoding the protein scaffolds that carried potential biomarker glycosites were up-regulated in triple negative vs luminal cell lines, and that a number of genes encoding fucosyl- or sialyltransferases were differentially expressed between the two subtypes, suggesting that alterations in glycosylation may also drive candidate identification. Notably, the glycoproteins from which these putative biomarker candidates were derived are involved in cancer-related processes. Thus, they may represent novel therapeutic targets for this aggressive tumor subtype.
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http://dx.doi.org/10.1021/pr201206wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383053PMC
April 2012

Immune interference in Mycobacterium tuberculosis intracellular iron acquisition through siderocalin recognition of carboxymycobactins.

ACS Chem Biol 2011 Dec 21;6(12):1327-31. Epub 2011 Oct 21.

The innate immune system antibacterial protein Siderocalin (Scn) binds ferric carboxymycobactin (CMB) and also several catecholate siderophores. Although the recognition of catecholates by Scn has been thoroughly investigated, the binding interactions of Scn with the full spectrum of CMB isoforms have not been studied. Here we show that Scn uses different binding modes for the limited subset of bound CMB isoforms, resulting in a range of binding affinities that are much weaker than other siderophore targets of Scn. Understanding the binding interaction between Scn and CMBs provides clues for the influence of Scn on mycobacterial iron acquisition.
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http://dx.doi.org/10.1021/cb200331gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241878PMC
December 2011

Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.

N Engl J Med 2011 Feb;364(7):616-26

Centre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom.

Background: Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population.

Methods: We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method).

Results: In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0×10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8×10(-9), P=5.6×10(-27), and P=5.2×10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2).

Conclusions: An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.
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http://dx.doi.org/10.1056/NEJMoa1009742DOI Listing
February 2011

Impact of [18F]fluorodeoxyglucose PET-CT staging on treatment planning in radiotherapy incorporating elective nodal irradiation for non-small-cell lung cancer: a prospective study.

Int J Radiat Oncol Biol Phys 2011 Jul 23;80(4):1008-14. Epub 2010 Jul 23.

Department of Radiation Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

Purpose: To evaluate prospectively how positron emission tomography (PET) information changes treatment plans for non-small-cell lung cancer (NSCLC) patients receiving or not receiving elective nodal irradiation (ENI).

Methods And Materials: One hundred consecutive patients referred for curative radiotherapy were included in the study. Treatment plans were carried out with CT data sets only. For stage III patients, mediastinal ENI was planned. Then, patients underwent PET-CT for diagnostic/planning purposes. PET/CT was fused with the CT data for final planning. New targets were delineated. For stage III patients with minimal N disease (N0-N1, single N2), the ENI was omitted in the new plans. Patients were treated according to the PET-based volumes and plans. The gross tumor volume (GTV)/planning tumor volume (PTV) and doses for critical structures were compared for both data sets. The doses for areas of potential geographical misses derived with the CT data set alone were compared in patients with and without initially planned ENI.

Results: In the 75 patients for whom the decision about curative radiotherapy was maintained after PET/CT, there would have been 20 cases (27%) with potential geographical misses by using the CT data set alone. Among them, 13 patients would receive ENI; of those patients, only 2 patients had the PET-based PTV covered by 90% isodose by using the plans based on CT alone, and the mean of the minimum dose within the missed GTV was 55% of the prescribed dose, while for 7 patients without ENI, it was 10% (p = 0.006). The lung, heart, and esophageal doses were significantly lower for plans with ENI omission than for plans with ENI use based on CT alone.

Conclusions: PET/CT should be incorporated in the planning of radiotherapy for NSCLC, even in the setting of ENI. However, if PET/CT is unavailable, ENI may to some extent compensate for an inadequate dose coverage resulting from diagnostic uncertainties.
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http://dx.doi.org/10.1016/j.ijrobp.2010.04.018DOI Listing
July 2011

HLA has strongest association with IgA nephropathy in genome-wide analysis.

J Am Soc Nephrol 2010 Oct 1;21(10):1791-7. Epub 2010 Jul 1.

The John Walls Renal Unit, Leicester General Hospital and Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, United Kingdom.

Demographic and family studies support the existence of a genetic contribution to the pathogenesis of IgA nephropathy, but results from genetic association studies of candidate genes are inconsistent. To systematically survey common genetic variation in this disease, we performed a genome-wide analysis in a cohort of patients with IgA nephropathy selected from the UK Glomerulonephritis DNA Bank. We used two groups of controls: parents of affected individuals and previously genotyped, unaffected, ancestry-matched individuals from the 1958 British Birth Cohort and the UK Blood Service. We genotyped 914 affected or family controls for 318,127 single nucleotide polymorphisms (SNPs). Filtering for low genotype call rates and inferred non-European ancestry left 533 genotyped individuals (187 affected children) for the family-based association analysis and 244 cases and 4980 controls for the case-control analysis. A total of 286,200 SNPs with call rates >95% were available for analysis. Genome-wide analysis showed a strong signal of association on chromosome 6p in the region of the MHC (P = 1 × 10(-9)). The two most strongly associated SNPs showed consistent association in both family-based and case-control analyses. HLA imputation analysis showed that the strongest association signal arose from a combination of DQ loci with some support for an independent HLA-B signal. These results suggest that the HLA region contains the strongest common susceptibility alleles that predispose to IgA nephropathy in the European population.
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http://dx.doi.org/10.1681/ASN.2010010076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013538PMC
October 2010

Simultaneous integrated boost radiotherapy for thyroid cancer.

Rep Pract Oncol Radiother 2010 19;15(6):155-60. Epub 2010 Nov 19.

Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland.

Aim: The purpose of this study was to examine the usefulness of using Simultaneous Integrated Boost (SIB) radiotherapy for thyroid cancer treatment.

Background: At our hospital a 3D Conformal RadioTherapy (3D-CRT) technique involving photon and electron beams for the treatment of thyroid cancer was often used.(1) High dose to the spinal canal was limiting the total dose of such a treatment. After investigation of Intensity Modulated Radiotherapy (IMRT) technique involving seven photon beams for first course of treatment(3) we decided to examine possibility of reducing treatment fractions by using SIB radiotherapy.

Material And Methods: Plans for 10 patients were studied. For each patient, IMRT plan for the first course of treatment (50 Gy for PTV), two plans for the second course of treatment (10 Gy for BOOST) and a SIB plan (50 Gy for PTV, 56 Gy for BOOST) were prepared. For all plans, comparisons of dose statistics for the PTV, BOOST, PTV without BOOST (defined as PTV without BOOST with 1 cm margin), spinal canal and Patient Outline (Body) was done.

Results: Minimum dose for BOOST is higher in the SIB technique than in the two course treatment. PTV without BOOST receives the same average dose in SIB and the 1st course IMRT - 50.10 Gy and 49.84 Gy, respectively. In the SIB technique, higher reduction of dose delivered to the spinal canal is possible (27 Gy compared with 30 Gy).

Conclusion: SIB therapy for thyroid cancer with relation to typical two course treatment is a good proposal of reducing the number of fractions with the same dose for BOOST and PTV without BOOST. Additionally, better sparing of the spinal canal is achieved.
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http://dx.doi.org/10.1016/j.rpor.2010.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863287PMC
December 2013

Characterization of a Bacillus subtilis transporter for petrobactin, an anthrax stealth siderophore.

Proc Natl Acad Sci U S A 2009 Dec 2;106(51):21854-9. Epub 2009 Dec 2.

Department of Chemistry, University of California, Berkeley, CA 94720-1460, USA.

Iron deprivation activates the expression of components of the siderophore-mediated iron acquisition systems in Bacillus subtilis, including not only the synthesis and uptake of its siderophore bacillibactin but also expression of multiple ABC transporters for iron scavenging using xenosiderophores. The yclNOPQ operon is shown to encode the complete transporter for petrobactin (PB), a photoreactive 3,4-catecholate siderophore produced by many members of the B. cereus group, including B. anthracis. Isogenic disruption mutants in the yclNOPQ transporter, including permease YclN, ATPase YclP, and a substrate-binding protein YclQ, are unable to use either PB or the photoproduct of FePB (FePB(nu)) for iron delivery and growth, in contrast to the wild-type B. subtilis. Complementation of the mutations with the copies of the respective genes restores this capability. The YclQ receptor binds selectively iron-free and ferric PB, the PB precursor, 3,4-dihydroxybenzoic acid (3,4-DHB), and FePB(nu) with high affinity; the ferric complexes are seen in ESI-MS, implying strong electrostatic interaction between the protein-binding pocket and siderophore. The first structure of a gram-positive siderophore receptor is presented. The 1.75-A crystal structure of YclQ reveals a bilobal periplasmic binding protein (PBP) fold consisting of two alpha/beta/alpha sandwich domains connected by a long alpha-helix with the binding pocket containing conserved positively charged and aromatic residues and large enough to accommodate FePB. Orthologs of the B. subtilis PB-transporter YclNOPQ in PB-producing Bacilli are likely contributors to the pathogenicity of these species and provide a potential target for antibacterial strategies.
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http://dx.doi.org/10.1073/pnas.0904793106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799803PMC
December 2009
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