BACKGROUND: Structure search is one of the valuable capabilities of small-molecule databases. Fingerprint-based screening methods are usually employed to enhance the search performance by reducing the number of calls to the verification procedure. In substructure search, fingerprints are designed to capture important structural aspects of the molecule to aid the decision about whether the molecule contains a given substructure. Currently available cartridges typically provide acceptable search performance for processing user queries, but do not scale satisfactorily with dataset size. RESULTS: We present Sachem, a new open-source chemical cartridge that implements two substructure search methods: The first is a performance-oriented reimplementation of substructure indexing based on the OrChem fingerprint, and the second is a novel method that employs newly designed fingerprints stored in inverted indices. We assessed the performance of both methods on small, medium, and large datasets containing 1, 10, and 94 million compounds, respectively. Comparison of Sachem with other freely available cartridges revealed improvements in overall performance, scaling potential and screen-out efficiency. CONCLUSIONS: The Sachem cartridge allows efficient substructure searches in databases of all sizes. The sublinear performance scaling of the second method and the ability to efficiently query large amounts of pre-extracted information may together open the door to new applications for substructure searches.

• Klíčová slova
• Inverted indices, Molecule cartridges, Small molecule databases, Substructure search,
• Publikační typ
• časopisecké články MeSH

We describe a new and model-independent Lévy imaging method of quality fits to the published datasets and reconstruct the amplitude of high-energy pp and p p ¯ elastic scattering processes. This method allows us to determine the excitation function of the shadow profile P(b), the elastic slope B(t) and the nuclear phase ϕ ( t ) functions of pp and p p ¯ collisions directly from the data. Surprisingly, notable qualitative differences in B(t) for pp and for p p ¯ collisions point towards an Odderon effect. As a by-product, we clearly identify the proton substructure with two different sizes at the ISR and LHC energies, that has striking similarity to a dressed quark (at the ISR) and a dressed diquark (at the LHC). We present model-independent results for the corresponding sizes and cross-sections for such a substructure for the existing data at different energies.

• Publikační typ
• časopisecké články MeSH

Understanding the role of parton mass and Casimir color factors in the quantum chromodynamics parton shower represents an important step in characterizing the emission properties of heavy quarks. Recent experimental advances in jet substructure techniques have provided the opportunity to isolate and characterize gluon emissions from heavy quarks. In this Letter, the first direct experimental constraint on the charm-quark splitting function is presented, obtained via the measurement of the groomed shared momentum fraction of the first splitting in charm jets, tagged by a reconstructed D^{0} meson. The measurement is made in proton-proton collisions at sqrt[s]=13 TeV, in the low jet transverse-momentum interval of 15≤p_{T}^{jet ch}<30 GeV/c where the emission properties are sensitive to parton mass effects. In addition, the opening angle of the first perturbative emission of the charm quark, as well as the number of perturbative emissions it undergoes, is reported. Comparisons to measurements of an inclusive-jet sample show a steeper splitting function for charm quarks compared with gluons and light quarks. Charm quarks also undergo fewer perturbative emissions in the parton shower, with a reduced probability of large-angle emissions.

• Publikační typ
• časopisecké články MeSH

Twelve Y-chromosomal short tandem repeats (Y-STR) (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a, DYS385b, DYS437, DYS438, and DYS439) included in the PowerPlex Y Kit (Promega Corporation, Madison, USA) were studied for 1750 unrelated males living in 14 regions of the Czech Republic. A total of 1148 different haplotypes were found. The overall haplotype diversity (HD) was determined as 0.998. Analysis of Molecular Variance (AMOVA) reveals non-significant distances between regions concerning their haplotype distribution, thus allowing to use the whole sample as a representative reference database of the Czech Republic. Median network analysis shows a remarkable bipartite composition of the Czech haplotypes, falling in distinct clusters with Eastern and Western European roots.

• MeSH
• databáze nukleových kyselin * MeSH
• DNA fingerprinting MeSH
• haplotypy * MeSH
• lidé MeSH
• lidský chromozom Y * MeSH
• polymerázová řetězová reakce MeSH
• populační genetika * MeSH
• tandemové repetitivní sekvence * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Stimulus-sensitive polymer drug conjugates based on high molecular weight N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers carrying doxorubicin via a pH-dependent cleavable bond (pHPMA-Dox) were previously shown to be able to overcome multi-drug resistance. Nevertheless, a tumor type dependent differential response was observed. Although an improved and more selective tumor accumulation of pHPMA-Dox is generally achieved due to the enhanced permeability and retention (EPR) effect, little is known about the fate of these conjugates upon entering the tumor tissue, which could explain the different responses. In this study, we compared in vitro and in vivo accumulation and Dox-activation of pHPMA-Dox in three cancer cell line models (1411HP, A2780cis, HT29) and derived xenograft tumors using a near-infrared fluorescence-labeled pHPMA-Dox conjugate. Firstly, cytotoxicity assays using different pH conditions proved a stepwise, pH-dependent increase in cytotoxic activity and revealed comparable sensitivity among the cell lines. Using multispectral fluorescence microscopy, we were able to track the distribution of drug and polymeric carrier simultaneously on cellular and histological levels. Microscopic analyses of cell monolayers confirmed the assumed mechanism of cell internalization of the whole conjugate followed by intracellular cleavage and nuclear accumulation of Dox in all three cell lines. In contrast, intratumoral distribution and drug release in xenograft tumors were completely different and were associated with different tissue substructures and microenvironments analyzed by Azan- and Hypoxisense®-staining. In 1411HP tumors, large vessels and less hypoxic/acidic microenvironments were associated with a pattern resulting from consistent tissue distribution and cellular uptake as whole conjugate followed by intracellular drug release. In A2780cis tumors, an inconsistent pattern of distribution partly resulting from premature drug release was associated with a more hypoxic/acidic microenvironment, compacted tumor tissue with compressed vessels and specific pre-damaged tissue structures. A completely different distribution pattern was observed in HT29 tumors, resulting from high accumulation of polymer in abundant fibrotic structures, with small embedded vessels featuring this tumor type together with pronounced premature drug release due to the strongly hypoxic/acidic microenvironment. In conclusion, the pattern of intratumoral distribution and drug release strongly depends on the tumor substructure and microenvironment and may result in different degrees of therapeutic efficacy. This reflects the pronounced heterogeneity observed in the clinical application of nanomedicines and can be exploited for the future design of such conjugates.

• Klíčová slova
• HPMA copolymer, chemotherapy resistance, pH-sensitive drug release, polymer drug conjugates, tumor microenvironment,
• MeSH
• buňky HT-29 MeSH
• doxorubicin aplikace a dávkování   chemie   farmakokinetika   MeSH
• fluorescenční barviva chemie   MeSH
• karbocyaniny chemie   MeSH
• koncentrace vodíkových iontů MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• methakryláty chemie   MeSH
• molekulová hmotnost MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• nosiče léků aplikace a dávkování   chemie   farmakokinetika   MeSH
• protinádorové látky aplikace a dávkování   chemie   farmakokinetika   MeSH
• tkáňová distribuce MeSH
• uvolňování léčiv MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• doxorubicin MeSH
• fluorescenční barviva MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• indotricarbocyanine MeSH Prohlížeč
• karbocyaniny MeSH
• methakryláty MeSH
• nosiče léků MeSH
• protinádorové látky MeSH

This letter presents a measurement of the nuclear modification factor of large-radius jets in sqrt[s_{NN}]=5.02 TeV Pb+Pb collisions by the ATLAS experiment. The measurement is performed using 1.72 nb^{-1} and 257 pb^{-1} of Pb+Pb and pp data, respectively. The large-radius jets are reconstructed with the anti-k_{t} algorithm using a radius parameter of R=1.0, by reclustering anti-k_{t} R=0.2 jets, and are measured over the transverse momentum (p_{T}) kinematic range of 158

• Publikační typ
• časopisecké články MeSH

MOTIVATION: The existing connections between large databases of chemicals, proteins, metabolites and assays offer valuable resources for research in fields ranging from drug design to metabolomics. Transparent search across multiple databases provides a way to efficiently utilize these resources. To simplify such searches, many databases have adopted semantic technologies that allow interoperable querying of the datasets using SPARQL query language. However, the interoperable interfaces of the chemical databases still lack the functionality of structure-driven chemical search, which is a fundamental method of data discovery in the chemical search space. RESULTS: We present a SPARQL service that augments existing semantic services by making interoperable substructure and similarity searches in small-molecule databases possible. The service thus offers new possibilities for querying interoperable databases, and simplifies writing of heterogeneous queries that include chemical-structure search terms. AVAILABILITY: The service is freely available and accessible using a standard SPARQL endpoint interface. The service documentation and user-oriented demonstration interfaces that allow quick explorative querying of datasets are available at https://idsm.elixir-czech.cz .

• Klíčová slova
• Interoperability, Linked data, Small molecule databases, Substructure search,
• Publikační typ
• časopisecké články MeSH

A search in an all-jet final state for new massive resonances decaying to W W , W Z , or Z Z boson pairs using a novel analysis method is presented. The analysis is performed on data corresponding to an integrated luminosity of 77.3 fb - 1 recorded with the CMS experiment at the LHC at a centre-of-mass energy of 13 Te . The search is focussed on potential narrow-width resonances with masses above 1.2 Te , where the decay products of each W or Z boson are expected to be collimated into a single, large-radius jet. The signal is extracted using a three-dimensional maximum likelihood fit of the two jet masses and the dijet invariant mass, yielding an improvement in sensitivity of up to 30% relative to previous search methods. No excess is observed above the estimated standard model background. In a heavy vector triplet model, spin-1 Z ' and W ' resonances with masses below 3.5 and 3.8 Te , respectively, are excluded at 95% confidence level. In a bulk graviton model, upper limits on cross sections are set between 27 and 0.2 fb for resonance masses between 1.2 and 5.2 Te , respectively. The limits presented in this paper are the best to date in the dijet final state.

• Klíčová slova
• CMS, Diboson resonances, Physics, Substructure,
• Publikační typ
• časopisecké články MeSH

Both copper and aluminum are widely applicable throughout a variety of industrial and commercial branches, however, joining them in a composite provides the possibility of combining all their advantageous properties in one material. This study investigates uniquely sequenced copper-aluminum clad composite wires, fabricated via rotary swaging technology. The composites were processed at 20 °C and 250 °C to a diameter of 5 mm. Structural observations and the determination of residual stress within both elements of the swaged wires were performed via electron microscopy; the experimental results were correlated with numerical predictions. As shown in the results, both the applied swaging force and temperature affected the plastic flow, which had a direct influence on residual stress and texture development; the Alsheath elements exhibited ideal rolling textures, whereas the Cuwires elements featured ideal shear texture orientation. The grains within both the Alsheath elements of the 5 mm composite wire were refined down to sub-micron size. Structural restoration also had a positive influence on residual stress.

• Klíčová slova
• clad composite, finite element analysis, residual stress, rotary swaging, substructure,
• Publikační typ
• časopisecké články MeSH

PURPOSE: Despite advancements in radiation techniques, concerns persist regarding the adverse effects of radiation therapy, particularly cardiotoxicity or radiation-induced heart disease. Recently, arrhythmogenic toxicity has come to the forefront-the impact of radiation therapy on the cardiac conduction system. Our objective was to conduct a dosimetric study and subsequently investigate the feasibility of optimizing the sinoatrial (SA) and atrioventricular (AV) nodes as organs at risk (OARs) in proton radiation therapy for non-small cell lung cancer with N3 disease. PATIENTS AND METHODS: Thirty-two non-small cell lung cancer patients with N3 disease undergoing proton radiation therapy were included. Sinoatrial and AV nodes, along with standard OARs, were delineated. Dosimetric analysis and optimization were performed using intensity-modulated proton therapy. RESULTS: Patients surpassing a predefined SA node dose threshold underwent dose optimization. Proton radiation therapy with pencil beam scanning demonstrated a significant reduction in SA and AV node doses without compromising target volume coverage or significant shift in the dose to other monitored OARs. CONCLUSION: Dose reduction to the SA and AV nodes for pencil beam scanning is a relatively simple task, and the reduction can be very substantial. Larger cohort studies and diverse radiotherapeutic modalities are needed for further validation and refinement of dose constraints.

• Klíčová slova
• Cardiac substructure, Cardiotoxicity, Conduction nodes, Non–small cell lung cancer, Proton therapy,
• Publikační typ
• časopisecké články MeSH