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Search results for: molecular targets
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Molecular Targets for Anticandidal Chemotherapy
PublicationA relatively small number of anticandidal chemotherapeutics used in clinical practice is at least in part consequence of a limited number of their molecular targets: ergosterol in the membrane, lanosterol demethylase, b(1!3) glucan synthase, and DNA/RNA biosynthesis. Much more potential novel targets have been revealed by the comparative genomic studies identifying essential genes unique for Candida albicans or resulted from recognition...
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Molecular targets for antifungals in amino acid and protein biosynthetic pathways
PublicationFungi cause death of over 1.5 million people every year, while cutaneous mycoses are among the most common infections in the world. Mycoses vary greatly in severity, there are long-term skin (ringworm), nail or hair infections (tinea capitis), recurrent like vaginal candidiasis or severe, life-threatening systemic, multiorgan infections. In the last few years, increasing importance is attached to the health and economic problems...
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New Peptide Based Fluconazole Conjugates with Expanded Molecular Targets
PublicationInfections of Candida spp. etiology are frequently treated with azole drugs. Among azoles, the most widely used in the clinical scenario remains fluconazole (FLC). Promising results in treatment of dangerous, systemic Candida infections demonstrate the advantages of combined therapies carried out with combinations of at least two different antifungal agents. Here, we report five conjugates composed of covalently linked FLC and...
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TIME-OF-FLIGHT DIFFERENTIAL ELECTRON SCATTERING FROM MOLECULAR TARGETS: BENCHMARK CROSS SECTIONS
PublicationWe report time-of-flight differential cross section (DCS) measurements for the electron impact excitation transition in H2. In this work, agreement between available theory and experiment is excellent overall, and marks a transition in electron molecule scattering where differential scattering of excitation is found to be in such precise agreement. We also prove that the newly built apparatus can be used for accurate measurement...
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Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets
PublicationNitric oxide (NO) is one of the most important molecules released by endothelial cells, and its antiatherogenic properties support cardiovascular homeostasis. Diminished NO bioavailability is a common hallmark of endothelial dysfunction underlying the patho‑ genesis of the cardiovascular disease. Vascular NO is synthesized by endothelial nitric oxide synthase (eNOS) from the substrate L‑arginine (L‑Arg), with tetrahydrobiopterin...
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Paweł Możejko dr hab.
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Evaluating experimental molecular physics studies of radiation damage in DNA*
PublicationThe field of Atomic and Molecular Physics (AMP) is a mature field exploring the spectroscopy, excitation, ionisation of atoms and molecules in all three phases. Understanding of the spectroscopy and collisional dynamics of AMP has been fundamental to the development and application of quantum mechanics and is applied across a broad range of disparate disciplines including atmospheric sciences, astrochemistry, combustion and environmental...
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Comparative molecular modelling of biologically active sterols
PublicationMembrane sterols are targets for a clinically important antifungal agent – amphotericin B. The relatively specific antifungal action of the drug is based on a stronger interaction of amphotericin B with fungal ergosterol than with mammalian cholesterol. Conformational space occupied by six sterols has been defined using the molecular dynamics method to establish if the conformational features correspond to the preferential interaction...
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Enzymes of the lysine biosynthetic pathway as targets for antifungals ?
PublicationSystemic infections caused by human pathogenic fungi in immunocompromized patients continue to be one of the important clinical problems. Limited availability of safe and efficacious antifungal chemotherapeutics and emerging resistance to existing drugs stimulates search for novel molecular targets for antifungals. The α-aminoadipate pathway (AAP) of L-lysine biosynthesis is unique in fungi and thus has been so far considered...
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Positron collisions with molecular hydrogen: cross sections and annihilation parameters calculated using theR-matrix with pseudo-states method
PublicationThe molecular R-matrix with pseudo-states (MRMPS) method is employed to study positron collisions with H2. The calculations employ pseudo-continuum orbital sets containing up to h (l = 5) functions. Use of these high l functions is found to give converged eigenphase sums. Below the positronium formation threshold, the calculated cross sections agree with other high-accuracy theories and generally with the measurements. Calculation...
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Molecular Recognition in Complexes of TRF Proteins with Telomeric DNA
PublicationTelomeres are specialized nucleoprotein assemblies that protect the ends of linear chromosomes. In humans and many other species, telomeres consist of tandem TTAGGG repeats bound by a protein complex known as shelterin that remodels telomeric DNA into a protective loop structure and regulates telomere homeostasis. Shelterin recognizes telomeric repeats through its two major components known as Telomere Repeat-Binding Factors, TRF1...
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Molecular basis and quantitative assessment of TRF1 and TRF2 protein interactions with TIN2 and Apollo peptides
PublicationShelterin is a six-protein complex (TRF1, TRF2, POT1, RAP1, TIN2, and TPP1) that also functions in smaller subsets in regulation and protection of human telomeres. Two closely related proteins, TRF1 and TRF2, make high-affinity contact directly with double-stranded telomeric DNA and serve as a molecular platform. Protein TIN2 binds to TRF1 and TRF2 dimer-forming domains, whereas Apollo makes interaction only with TRF2. To elucidate...
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Positron-electron correlation-polarization potentials for the calculation of positron collisions with atoms and molecules
PublicationWe present correlation-polarization potentials for the calculation of scattering cross sections of positrons with atoms and molecules. The potentials are constructed from a short-range correlation term and a long-range polarization term. For the short-range correlation term we present four different potentials that are derived from multi-component density functionals. For the long-range polarization term we employ a multi-term...
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Mechanism of Binding of Antifungal Antibiotic Amphotericin B to Lipid Membranes: An Insight from Combined Single-Membrane Imaging, Microspectroscopy, and Molecular Dynamics
PublicationAmphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited because of its severe toxic side effects. At the same time, the lack of a well-defined mechanism of selectivity hampers the efforts to rationally design safer derivatives. As the drug primarily targets the biomembranes of both fungi and humans, new insights into the...
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Targeting DNA Topoisomerase II in Antifungal Chemotherapy.
PublicationTopoisomerase inhibitors have been in use clinically for the treatment of several diseases for decades. Although those enzymes are significant molecular targets in antibacterial and anticancer chemotherapy very little is known about the possibilities to target fungal topoisomerase II (topo II). Raising concern for the fungal infections, lack of effective drugs and a phenomenon of multidrug resistance underlie a strong need to expand...
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Sławomir Milewski prof. dr hab. inż.
PeopleSławomir Milewski, born in 1955 in Puck, Poland, graduated in 1979 in Chemistry from the Faculty of Chemistry, Gdańsk University of Technology (GUT). In 1984 was employed at the Department of Pharmaceutical Technology and Biochemistry. In 1985 he got his PhD, in 1994 became a DSc (habilitation) and in 2002 got the professorship in chemical sciences. Currently he is a full professor and Head of the Department of Pharmaceutical Technology...
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Polarisation effects in low-energy positron–molecule scattering
PublicationThe UK molecular R-matrix method has been adapted to treat positron collisions from polyatomic targets. A simple empirical enhancement factor which corrects for the underestimation of electron–positron polarisation and correlation effects in the calculations performed with the static-plus-polarization model at low scattering energies is presented. Application of this model to positron scattering from carbon dioxide at energies...
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Identification and cloning of C. albicans SC5314 genes encoding L-methionine biosynthetic pathway enzymes.
Open Research DataEnzymes of fungal L-methionine biosynthetic pathway: homoserine O-acetyltransferase (Met2p), O-acetylhomoserine sulfhydrylase (Met15p) and cystathionine-γ-synthase (Str2p) could be exploited as molecular targets for antifungal chemotherapy. The goal of the study was to identify and clone genes encoding mentioned above enzymes. MET2, MET15 and STR2 genes...
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Phase transition of a dimorphic fungus Penicillium marneffei
PublicationPenicillium marneffei is a pathogenic fungus that afflicts immunocompromised individuals who live or travel in Southeast Asia. This species is unique, because it is the only dimorphic member of the genus Penicillium. Dimorphism results from a process, termed phase transition, which is regulated by temperature of incubation. At room temperature, the fungus grows filamentously (mould phase), but at body temperature (37°C), a uninucleate...
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Recent total cross section measurements in electron scattering from molecules
PublicationThe grand-total cross sections (TCSs) for electron scattering from a range of molecules, measured over the period 2009-2019 in various laboratories, with the use of different electron transmission systems, are reviewed. Where necessary, the presented TCS data are also compared to earlier results. Collection of investigated molecular targets (biomolecules, biofuels, molecules of technological application,hydrocarbons) reflects their...
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Modeling protein structures with the coarse-grained UNRES force field in the CASP14 experiment
PublicationThe UNited RESidue (UNRES) force field was tested in the 14th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP14), in which larger oligomeric and multimeric targets were present compared to previous editions. Three prediction modes were tested (i) ab initio (the UNRES group), (ii) contact-assisted (the UNRES- contact group), and (iii) template-assisted (the UNRES-template...
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Acid–Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis
PublicationUnsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected 3D cancer spheroid growth and their cellular uptake was selectively modulated by quantum dots. UAs were shown to undergo metabolic...
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HDAC Inhibitors: Innovative Strategies for Their Design and Applications
PublicationHistone deacetylases (HDACs) are a large family of epigenetic metalloenzymes that are involved in gene transcription and regulation, cell proliferation, differentiation, migration, and death, as well as angiogenesis. Particularly, disorders of the HDACs expression are linked to the development of many types of cancer and neurodegenerative diseases, making them interesting molecular targets for the design of new efficient drugs...
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Antifungal Effect of Penicillamine Due to the Selective Targeting of L-Homoserine O-Acetyltransferase
PublicationDue to the apparent similarity of fungal and mammalian metabolic pathways, the number of established antifungal targets is low, and the identification of novel ones is highly desirable. The results of our studies, presented in this work, indicate that the fungal biosynthetic pathway of L-methionine, an amino acid essential for humans, seems to be an attractive perspective. The MET2 gene from Candida albicans encoding L-homoserine...
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L1 Cell Adhesion Molecule Overexpression Down Regulates Phosphacan and Up Regulates Structural Plasticity-Related Genes Rostral and Caudal to the Complete Spinal Cord Transection
PublicationL1 cell adhesion molecule (L1CAM) supports spinal cord cellular milieu after contusion and compression lesions, contributing to neuroprotection, promoting axonal outgrowth, and reducing outgrowth-inhibitory molecules in lesion proximity. We extended investigations into L1CAM molecular targets and explored long-distance effects of L1CAM rostral and caudal to complete spinal cord transection (SCT) in...
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Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants
PublicationThe genome feature of SARS-CoV-2 leads the virus to mutate and creates new variants of concern. Tackling viral mutations is also an important challenge for the development of a new vaccine. Accordingly, in the present study, we undertook to identify B- and T-cell epitopes with immunogenic potential for eliciting responses to SARS-CoV-2, using computational approaches and its tailoring to coronavirus variants. A total of 47 novel...
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Receptor for advanced glycation end‐products: Biological significance and imaging applications
PublicationThe receptor for advanced glycation end-products (RAGE or AGER) is a transmembrane, immunoglobulin-like receptor that, due to its multiple isoform structures, binds to a diverse range of endo- and exogenous ligands. RAGE activation caused by the ligand binding initiates a cascade of complex pathways associated with producing free radicals, such as reactive nitric oxide and oxygen species, cell proliferation, and immunoinflammatory...
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Characterization of two aminotransferases from Candida albicans
PublicationAminoadipate aminotransferase (AmAA) is an enzyme of α-aminoadipate pathway (AAP) for l-lysine biosynthesis. AmAA may also participated in biosynthesis or degradation of aromatic amino acids and in d-tryptophan based pigment production. The AAP is unique for fungal microorganisms. Enzymes involved in this pathway have specific structures and properties. These features can be used as potential molecular markers. Enzymes catalyzing...
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New Approaches for Escherichia coli Genotyping
PublicationEasy-to-perform, fast, and inexpensive methods of differentiation of Escherichia coli strains beyond the species level are highly required. Herein two new, original tools for genotyping of E. coli isolates are proposed. The first of the developed method, a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) test uses a highly variable fliC gene, encoding the H antigen as a molecular target. The designing...
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A review on computer‐aided chemogenomics and drug repositioning for rational COVID ‐19 drug discovery
PublicationApplication of materials capable of energy harvesting to increase the efficiency and environmental adaptability is sometimes reflected in the ability of discovery of some traces in an environment―either experimentally or computationally―to enlarge practical application window. The emergence of computational methods, particularly computer-aided drug discovery (CADD), provides ample opportunities for the rapid discovery and development...
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Proteomic and Metabolomic Changes in Psoriasis Preclinical and Clinical Aspects
PublicationSkin diseases such as psoriasis (Ps) and psoriatic arthritis (PsA) are immune-mediated inflammatory diseases. Overlap of autoinflammatory and autoimmune conditions hinders diagnoses and identifying personalized patient treatments due to different psoriasis subtypes and the lack of verified biomarkers. Recently, proteomics and metabolomics have been intensively investigated in a broad range of skin diseases with the main purpose...
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Cross sections for electron collision with pyridine [C5H5N] molecule
PublicationThe absolute grand -total cross section (TCS) for electron scattering from pyridine, C5H5N, molecules has been measured at impact energies from 0.6 to 300 eV in the linear electron-transmission experiment. The obtained TCS energy dependence appears to be typical for targets of high electric-dipole moment; the cross section generally decreases with rising energy, except for the 3–20 eV range, where a broad enhancement peaked near...
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Use of the UNRES force field in template-assisted prediction of protein structures and the refinement of server models: Test with CASP12 targets
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Piperine Targets Different Drug Resistance Mechanisms in Human Ovarian Cancer Cell Lines Leading to Increased Sensitivity to Cytotoxic Drugs
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c-Myc Protein Level Affected by Unsymmetrical Bisacridines Influences Apoptosis and Senescence Induced in HCT116 Colorectal and H460 Lung Cancer Cells
PublicationUnsymmetrical bisacridines (UAs) are highly active antitumor compounds. They contain in their structure the drugs previously synthesized in our Department: C-1311 and C-1748. UAs exhibit different properties than their monomer components. They do not intercalate to dsDNA but stabilize the G-quadruplex structures, particularly those of the MYC and KRAS genes. Since MYC and KRAS are often mutated and constitutively expressed in cancer...
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Adaptation of radar software to work with ambiguous distance measurement
PublicationA software extension for radar stations designed to work in the low-PRF mode that allows them to correctly measure range to targets outside of their instrumented range, is proposed. The solution does not require substantial modifications of the radar software. Additionally, we describe tools that allow one to simulate the output of a low-PRF radar observing targets that are outside its instrumented range. The proposed approach...
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How do sterols determine the antufungal activitiy of amphotericin B? Free energy of binding between the drug and its membrane targets.
PublicationAmphotericin B (AmB) is a well-known polyene antibiotic used to treat systemic fungal infections. It is commonly accepted that the presence of sterols in the membrane is essential for the AmB biological activity, that is, for the formation of transmembrane ion channels. The selective toxicity of AmB for fungal cells is attributed to the fact that it is more potent against fungal cell membranes containing ergosterol than against...
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A Target Information Display for Visualising Collision Avoidance Manoeuvres in Various Visibility Conditions
PublicationThe paper introduces a new approach to displaying information on targets. The proposed display visualises three types of information: targets’ motion parameters (typical for target tracking), combinations of own course and speed which collide with those targets (typical for Collision Threat Parameters Area display by Lenart (1983)) and combinations of own course and speed which are not compliant with COLREGS in this case (based...
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Prediction of protein assemblies, the next frontier: The CASP14‐CAPRI experiment
PublicationWe present the results for CAPRI Round 50, the 4th joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of 12 targets, including 6 dimers, 3 trimers, and 3 higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly...
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Scattering of electrons by a 1,2-butadiene (C4H6) molecule: measurements and calculations
PublicationWe present the results of experimental and theoretical study on electron collisions with a 1,2-butadiene (H2C=C=CHCH3) molecule. Absolute grand-total cross sections (TCSs) were measured using a linear electron-transmission method for collision energies in the 0.5–300 eV range. Two distinct features in the TCS energy curve were detected: a narrow peak located at 2.3 eV and a broad enhancement centered around 9 eV. We attributed...
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Determining and visualizing safe motion parameters of a ship navigating in severe weather conditions
PublicationThe paper presents a method of determining, organizing and displaying ship collision avoidance information, which is based on the Collision Threat Parameters Area (CTPA) technique. The method makes it possible to visualize navigational threats as well as possible collision avoidance manoeuvres. The solution is focused on supporting navigation in severe weather conditions. Normally collision avoidance decisions are made taking into...
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Protective Effect of Aronia Melanocarpa Polyphenols on Cadmium Accumulation in the Body: A Study in a Rat Model of Human Exposure to this Metal
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Aqueous Extracts of Selected Potentilla Species Modulate Biological Activity of Human Normal Colon Cells
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New Insights into Dietary Supplements Used in Sport: Active Substances, Pharmacological and Side Effects
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Complexation of Bioelements and Toxic Metals by Polyphenolic Compounds - Implications for Health
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Antioxidants as a Potential Preventive and Therapeutic Strategy for Cadmium
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Potential of Liquid Biopsy in Papillary Thyroid Carcinoma in Context of miRNA, BRAF and p53 Mutation
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Targeting shelterin proteins for cancer therapy.
PublicationAs a global health challenge, cancer prompts continuous exploration for innovative therapies that are also based on new targets. One promising avenue is targeting the shelterin protein complex, a safeguard for telomeres crucial in preventing DNA damage. The role of shelterin in modulating ataxia- telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases, key players in the DNA damage response (DDR),...
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Conditions for Multiple Acquisition of Echoes from Stationary Targets in Successive Transmissions of Active Sonars
PublicationIn echolocation, the highest possible number of contacts with a detected target is clearly decisive on the possibilities of echo processing to optimise the estimation of distinctive characteristics of the observed target. In hydrolocation, the slow propagation of acoustic waves in water reduces the number of contacts of echosounders and sonars with detected targets. The article considers model conditions for acquiring multiple...
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Application of Maximum Lenght Sequence in Silent Sonar
PublicationSilent sonars are designed to reduce the distance over which their sounding pulses can be detected by intercept sonars. In order to meet this objective, we can use periodical sounding signals that have low power, a very long duration and wide spectrum. If used in the silent sonar's receiver, matched filtration ensures very good detection of motionless or slow moving targets. However, it is more difficult to detect echo signals...