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Article ; Online: Current therapeutic targets and multifaceted physiological impacts of caffeine.

Song, Xinjie / Kirtipal, Nikhil / Lee, Sunjae / Malý, Petr / Bharadwaj, Shiv

2023 Volume 37, Issue 12, Page(s) 5558–5598

Abstract: Caffeine, which shares consubstantial structural similarity with purine adenosine, has been demonstrated as a nonselective adenosine receptor antagonist for eliciting most of the biological functions at physiologically relevant dosages. Accumulating ... ...

Abstract	Caffeine, which shares consubstantial structural similarity with purine adenosine, has been demonstrated as a nonselective adenosine receptor antagonist for eliciting most of the biological functions at physiologically relevant dosages. Accumulating evidence supports caffeine's beneficial effects against different disorders, such as total cardiovascular diseases and type 2 diabetes. Conversely, paradoxical effects are also linked to caffeine ingestion in humans including hypertension-hypotension and tachycardia-bradycardia. These observations suggest the association of caffeine action with its ingested concentration and/or concurrent interaction with preferential molecular targets to direct explicit events in the human body. Thus, a coherent analysis of the functional targets of caffeine, relevant to normal physiology, and disease pathophysiology, is required to understand the pharmacology of caffeine. This review provides a broad overview of the experimentally validated targets of caffeine, particularly those of therapeutic interest, and the impacts of caffeine on organ-specific physiology and pathophysiology. Overall, the available empirical and epidemiological evidence supports the dose-dependent functional activities of caffeine and advocates for further studies to get insights into the caffeine-induced changes under specific conditions, such as asthma, DNA repair, and cancer, in view of its therapeutic applications.
MeSH term(s)	Humans ; Caffeine/pharmacology ; Caffeine/chemistry ; Diabetes Mellitus, Type 2 ; Hypertension/drug therapy ; Cardiovascular Diseases
Chemical Substances	Caffeine (3G6A5W338E)
Language	English
Publishing date	2023-09-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	639136-9
ISSN	1099-1573 ; 0951-418X
ISSN (online)	1099-1573
ISSN	0951-418X
DOI	10.1002/ptr.8000
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Article ; Online: NSCLC: from tumorigenesis, immune checkpoint misuse to current and future targeted therapy.

Raskova Kafkova, Leona / Mierzwicka, Joanna M / Chakraborty, Prosenjit / Jakubec, Petr / Fischer, Ondrej / Skarda, Jozef / Maly, Petr / Raska, Milan

Frontiers in immunology

2024 Volume 15, Page(s) 1342086

Abstract: Non-small cell lung cancer (NSCLC) is largely promoted by a multistep tumorigenesis process involving various genetic and epigenetic alterations, which essentially contribute to the high incidence of mortality among patients with NSCLC. Clinical ... ...

Abstract	Non-small cell lung cancer (NSCLC) is largely promoted by a multistep tumorigenesis process involving various genetic and epigenetic alterations, which essentially contribute to the high incidence of mortality among patients with NSCLC. Clinical observations revealed that NSCLC also co-opts a multifaceted immune checkpoint dysregulation as an important driving factor in NSCLC progression and development. For example, a deregulated PI3K/AKT/mTOR pathway has been noticed in 50-70% of NSCLC cases, primarily modulated by mutations in key oncogenes such as ALK, EGFR, KRAS, and others. Additionally, genetic association studies containing patient-specific factors and local reimbursement criteria expose/reveal mutations in EGFR/ALK/ROS/BRAF/KRAS/PD-L1 proteins to determine the suitability of available immunotherapy or tyrosine kinase inhibitor therapy. Thus, the expression of such checkpoints on tumors and immune cells is pivotal in understanding the therapeutic efficacy and has been extensively studied for NSCLC treatments. Therefore, this review summarizes current knowledge in NSCLC tumorigenesis, focusing on its genetic and epigenetic intricacies, immune checkpoint dysregulation, and the evolving landscape of targeted therapies. In the context of current and future therapies, we emphasize the significance of antibodies targeting PD-1/PD-L1 and CTLA-4 interactions as the primary therapeutic strategy for immune system reactivation in NSCLC. Other approaches involving the promising potential of nanobodies, probodies, affibodies, and DARPINs targeting immune checkpoints are also described; these are under active research or clinical trials to mediate immune regulation and reduce cancer progression. This comprehensive review underscores the multifaceted nature, current state and future directions of NSCLC research and treatment.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; B7-H1 Antigen/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins p21(ras) ; Cell Transformation, Neoplastic ; Carcinogenesis ; Receptor Protein-Tyrosine Kinases/metabolism ; ErbB Receptors/metabolism
Chemical Substances	B7-H1 Antigen ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2024-02-07
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1342086
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Article ; Online: Secretion and surface display of binders of IL-23/IL-17 cytokines and their receptors in Lactococcus lactis as a therapeutic approach against inflammation.

Plavec, Tina Vida / Klemenčič, Kaja / Kuchař, Milan / Malý, Petr / Berlec, Aleš

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2023 Volume 190, Page(s) 106568

Abstract: The cytokine IL-23 activates the IL-23 receptor (IL-23R) and stimulates the differentiation of naïve T helper (Th) cells into a Th17 cell population that secretes inflammatory cytokines and chemokines. This IL-23/Th17 proinflammatory axis drives ... ...

Abstract	The cytokine IL-23 activates the IL-23 receptor (IL-23R) and stimulates the differentiation of naïve T helper (Th) cells into a Th17 cell population that secretes inflammatory cytokines and chemokines. This IL-23/Th17 proinflammatory axis drives inflammation in Crohn's disease and ulcerative colitis and represents a therapeutic target of monoclonal antibodies. Non-immunoglobulin binding proteins based on the Streptococcus albumin-binding domain (ABD) provide a small protein alternative to monoclonal antibodies. They can be readily expressed in bacteria. Lactococcus lactis is a safe lactic acid bacterium that has previously been engineered as a vector for the delivery of recombinant therapeutic proteins to mucosal surfaces. Here, L. lactis was engineered to display or secrete ABD-variants against the IL-17 receptor (IL-17R). Its expression and functionality were confirmed with flow cytometry using specific antibody and recombinant IL-17R, respectively. In addition, L. lactis were engineered into multifunctional bacteria that simultaneously express two binders from pNBBX plasmid. First, binders of IL-17R were combined with binder of IL-17. Second, binders of IL-23R were combined with binders of IL-23. The dual functionality of the bacteria was confirmed by flow cytometry using corresponding targets, namely the recombinant receptors IL-17R and IL-23R or the p19 subunit of IL-23. Binding of IL-17 was confirmed by ELISA. With the latter, 97% of IL-17 was removed from solution by 2 × 10
MeSH term(s)	Humans ; Cytokines/metabolism ; Interleukin-17/metabolism ; Lactococcus lactis/genetics ; Lactococcus lactis/metabolism ; Immunologic Factors ; Inflammation ; Carrier Proteins/metabolism ; Recombinant Proteins/metabolism ; Albumins/metabolism ; Interleukin-23/chemistry ; Interleukin-23/metabolism ; Antibodies, Monoclonal
Chemical Substances	Cytokines ; Interleukin-17 ; Immunologic Factors ; Carrier Proteins ; Recombinant Proteins ; Albumins ; Interleukin-23 ; Antibodies, Monoclonal
Language	English
Publishing date	2023-08-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2023.106568
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Zs.A 3705: Show issues

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Article: Ultrafast Dynamics of Valley-Polarized Excitons in WSe

Koutenský, Petr / Slobodeniuk, Artur / Bartoš, Miroslav / Trojánek, František / Malý, Petr / Kozák, Martin

Nanomaterials (Basel, Switzerland)

2023 Volume 13, Issue 7

Abstract: We report on the experimental investigation of the ultrafast dynamics of valley-polarized excitons in monolayer WSe2 using transient reflection spectroscopy with few-cycle laser pulses with 7 fs duration. We observe that at room temperature, the ... ...

Abstract	We report on the experimental investigation of the ultrafast dynamics of valley-polarized excitons in monolayer WSe2 using transient reflection spectroscopy with few-cycle laser pulses with 7 fs duration. We observe that at room temperature, the anisotropic valley population of excitons decays on two different timescales. The shorter decay time of approximately 120 fs is related to the initial hot exciton relaxation related to the fast direct recombination of excitons from the radiative zone, while the slower picosecond dynamics corresponds to valley depolarization induced by Coloumb exchange-driven transitions of excitons between two inequivalent valleys.
Language	English
Publishing date	2023-03-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662255-5
ISSN	2079-4991
ISSN	2079-4991
DOI	10.3390/nano13071207
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Article: Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy.

Kumar, Geethu S / Moustafa, Mahmoud / Sahoo, Amaresh Kumar / Malý, Petr / Bharadwaj, Shiv

Life (Basel, Switzerland)

2022 Volume 12, Issue 5

Abstract: Several therapeutic monoclonal antibodies approved by the FDA are available against the PD-1/PD-L1 (programmed death 1/programmed death ligand 1) immune checkpoint axis, which has been an unprecedented success in cancer treatment. However, existing ... ...

Abstract	Several therapeutic monoclonal antibodies approved by the FDA are available against the PD-1/PD-L1 (programmed death 1/programmed death ligand 1) immune checkpoint axis, which has been an unprecedented success in cancer treatment. However, existing therapeutics against PD-L1, including small molecule inhibitors, have certain drawbacks such as high cost and drug resistance that challenge the currently available anti-PD-L1 therapy. Therefore, this study presents the screening of 32,552 compounds from the Natural Product Atlas database against PD-L1, including three steps of structure-based virtual screening followed by binding free energy to refine the ideal conformation of potent PD-L1 inhibitors. Subsequently, five natural compounds, i.e., Neoenactin B1, Actinofuranone I, Cosmosporin, Ganocapenoid A, and 3-[3-hydroxy-4-(3-methylbut-2-enyl)phenyl]-5-(4-hydroxybenzyl)-4-methyldihydrofuran-2(3H)-one, were collected based on the ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and binding free energy (>−60 kcal/mol) for further computational investigation in comparison to co-crystallized ligand, i.e., JQT inhibitor. Based on interaction mapping, explicit 100 ns molecular dynamics simulation, and end-point binding free energy calculations, the selected natural compounds were marked for substantial stability with PD-L1 via intermolecular interactions (hydrogen and hydrophobic) with essential residues in comparison to the JQT inhibitor. Collectively, the calculated results advocate the selected natural compounds as the putative potent inhibitors of PD-L1 and, therefore, can be considered for further development of PD-L1 immune checkpoint inhibitors in cancer immunotherapy.
Language	English
Publishing date	2022-04-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life12050659
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Article ; Online: IL-6 and its role in IgA nephropathy development.

Groza, Yaroslava / Jemelkova, Jana / Kafkova, Leona Raskova / Maly, Petr / Raska, Milan

Cytokine & growth factor reviews

2022 Volume 66, Page(s) 1–14

Abstract: IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are ... ...

Abstract	IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes. Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria. This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.
MeSH term(s)	Galactose/metabolism ; Glomerular Mesangium/metabolism ; Glomerulonephritis, IGA/metabolism ; Glomerulonephritis, IGA/pathology ; Humans ; Immunoglobulin A/metabolism ; Interleukin-6/metabolism
Chemical Substances	Immunoglobulin A ; Interleukin-6 ; Galactose (X2RN3Q8DNE)
Language	English
Publishing date	2022-04-20
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1330534-7
ISSN	1879-0305 ; 1359-6101
ISSN (online)	1879-0305
ISSN	1359-6101
DOI	10.1016/j.cytogfr.2022.04.001
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Zs.A 2653: Show issues

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Article ; Online: Light emission dynamics of silicon vacancy centers in a polycrystalline diamond thin film.

Trojánek, František / Hamráček, Karol / Hanák, Martin / Varga, Marián / Kromka, Alexander / Babčenko, Oleg / Ondič, Lukáš / Malý, Petr

Nanoscale

2023 Volume 15, Issue 6, Page(s) 2734–2738

Abstract: Diamond thin films can be, at a relatively low-cost, prepared with a high-density of light-emitting negatively charged silicon vacancy (SiV) centers, which opens up the possibility of their application in photonics or sensing. The films are composed of ... ...

Abstract	Diamond thin films can be, at a relatively low-cost, prepared with a high-density of light-emitting negatively charged silicon vacancy (SiV) centers, which opens up the possibility of their application in photonics or sensing. The films are composed of diamond grains with both the SiV centers and sp
Language	English
Publishing date	2023-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2515664-0
ISSN	2040-3372 ; 2040-3364
ISSN (online)	2040-3372
ISSN	2040-3364
DOI	10.1039/d2nr05470a
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Article ; Online: Neutrophil Extracellular Traps and Thrombolysis Resistance: New Insights for Targeting Therapies.

Mengozzi, Luca / Barison, Ilaria / Malý, Martin / Lorenzoni, Giulia / Fedrigo, Marny / Castellani, Chiara / Gregori, Dario / Malý, Petr / Matěj, Radoslav / Toušek, Petr / Widimský, Petr / Angelini, Annalisa

Stroke

2024 Volume 55, Issue 4, Page(s) 963–971

Abstract: Background: Thrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical ... ...

Abstract	Background: Thrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical thrombectomy, estimate the age and organization of thrombi, and evaluate associations with the use of thrombolysis, antiplatelets, and heparin. Methods: This retrospective observational study involved 72 samples (44 from cerebral and 28 coronary arteries), which were stained with hematoxylin and eosin, anti-NE (neutrophil elastase) antibody, and anti-histone H2B (histone H2B) antibody, representing different components in NET formation, all detectable during the later stages of NETosis, for histochemical and digital quantification of NET content. The histological and morphological evaluations of the specimens were correlated, through univariate and mediation analyses, with clinical information and therapy administered before intervention. Results: The results demonstrated that the composition of cerebral and coronary thrombi differs, and there were significantly more lytic cerebral thrombi than coronary thrombi (66% versus 14%; Conclusions: The age of the thrombus is the driving force for NET content, which correlates with impaired clinical outcomes. The therapy that is currently administered does not modify NET content. This study supports the need to investigate new pharmacological approaches added to thrombolysis to prevent NET formation or enhance their disruption, such as recombinant human DNase I (deoxyribonuclease I).
MeSH term(s)	Humans ; Extracellular Traps/metabolism ; Neutrophils/metabolism ; Thrombosis/drug therapy ; Thrombosis/metabolism ; Histones/metabolism ; Thrombolytic Therapy ; Heparin
Chemical Substances	Histones ; Heparin (9005-49-6)
Language	English
Publishing date	2024-03-11
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	80381-9
ISSN	1524-4628 ; 0039-2499 ; 0749-7954
ISSN (online)	1524-4628
ISSN	0039-2499 ; 0749-7954
DOI	10.1161/STROKEAHA.123.045225
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Zs.A 448: Show issues

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Article: Understanding on the possible routes for SARS CoV-2 invasion via ACE2 in the host linked with multiple organs damage

Kirtipal, Nikhil / Kumar, Sanjay / Dubey, Sumit Kumar / Dwivedi, Vivek Dhar / Gireesh Babu, K. / Malý, Petr / Bharadwaj, Shiv

Infection, genetics, and evolution. 2022 Apr., v. 99

2022

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accountable for causing the coronavirus diseases 2019 (COVID-19), is already declared as a pandemic disease globally. Like previously reported SARS-CoV strain, the novel SARS-CoV-2 also ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accountable for causing the coronavirus diseases 2019 (COVID-19), is already declared as a pandemic disease globally. Like previously reported SARS-CoV strain, the novel SARS-CoV-2 also initiates the viral pathogenesis via docking viral spike-protein with the membranal angiotensin-converting enzyme 2 (ACE2) — a receptor on variety of cells in the human body. Therefore, COVID-19 is broadly characterized as a disease that targets multiple organs, particularly causing acute complications via organ-specific pathogenesis accompanied by destruction of ACE2⁺ cells, including alveolus, cardiac microvasculature, endothelium, and glomerulus. Under such circumstances, the high expression of ACE2 in predisposing individuals associated with anomalous production of the renin-angiotensin system (RAS) may promote enhanced viral load in COVID-19, which comparatively triggers excessive apoptosis. Furthermore, multi-organ injuries were found linked to altered ACE2 expression and inequality between the ACE2/angiotensin-(1–7)/mitochondrial Ang system (MAS) and renin-angiotensin-system (RAS) in COVID-19 patients. However, the exact pathogenesis of multi-organ damage in COVID-19 is still obscure, but several perspectives have been postulated, involving altered ACE2 expression linked with direct/indirect damages by the virus-induced immune responses, such as cytokinin storm. Thus, insights into the invasion of a virus with respect to ACE2 expression site can be helpful to simulate or understand the possible complications in the targeted organ during viral infection. Hence, this review summarizes the multiple organs invasion by SARS CoV-2 linked with ACE2 expression and their consequences, which can be helpful in the management of the COVID-19 pathogenesis under life-threatening conditions.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; apoptosis ; cytokinins ; endothelium ; evolution ; genetics ; humans ; infection ; pandemic ; pathogenesis ; peptidyl-dipeptidase A ; renin-angiotensin system ; storms ; viral load ; viruses
Language	English
Dates of publication	2022-04
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2037068-4
ISSN	1567-1348
ISSN	1567-1348
DOI	10.1016/j.meegid.2022.105254
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: High harmonic generation enhanced by magnetic dipole resonance in an amorphous silicon metasurface.

Peterka, Pavel / Šobáň, Zbyněk / Trojánek, František / Malý, Petr / Kozák, Martin

Optics express

2020 Volume 31, Issue 4, Page(s) 6401–6410

Abstract: We report on the enhancement of high harmonic generation (HHG) yield in a metasurface consisting of amorphous silicon disks in a periodic array on an insulator substrate. The structure was designed and optimized using the finite-difference time-domain ... ...

Abstract	We report on the enhancement of high harmonic generation (HHG) yield in a metasurface consisting of amorphous silicon disks in a periodic array on an insulator substrate. The structure was designed and optimized using the finite-difference time-domain method for the maximum enhancement, which reaches the factor of 20-times compared to the unstructred surface. The local field is enhanced by a broadband magnetic resonance mode allowing to use ultrashort laser pulses with Fourier transform limit down to 40 fs. Due to the anisotropic structure of the metasurface, both the local-field enhancement and the HHG yield show strong polarization anisotropy.
Language	English
Publishing date	2020-09-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1491859-6
ISSN	1094-4087 ; 1094-4087
ISSN (online)	1094-4087
ISSN	1094-4087
DOI	10.1364/OE.481199
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