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Article ; Online: Dengue Virus Infects Human Skin Langerhans Cells through Langerin for Dissemination to Dendritic Cells.

Helgers, Leanne C / Keijzer, Nadia C H / van Hamme, John L / Sprokholt, Joris K / Geijtenbeek, Teunis B H

The Journal of investigative dermatology

2023 Volume 144, Issue 5, Page(s) 1099–1111.e3

Abstract: Dengue virus (DENV) is the most disease-causative flavivirus worldwide. DENV as a mosquito-borne virus infects human hosts through the skin; however, the initial target cells in the skin remain unclear. In this study, we have investigated whether ... ...

Abstract	Dengue virus (DENV) is the most disease-causative flavivirus worldwide. DENV as a mosquito-borne virus infects human hosts through the skin; however, the initial target cells in the skin remain unclear. In this study, we have investigated whether epidermal Langerhans cells (LCs) play a role in DENV acquisition and dissemination. We have used a human epidermal ex vivo infection model as well as isolated LCs to investigate infection by DENV. Notably, both immature and mature LCs were permissive to DENV infection in vitro and ex vivo, and infection was dependent on C-type lectin receptor langerin because blocking antibodies against langerin significantly reduced DENV infection in vitro and ex vivo. DENV-infected LCs efficiently transmitted DENV to target cells such as dendritic cells. Moreover, DENV exposure increased the migration of LCs from epidermal explants. These results strongly suggest that DENV targets epidermal LCs for infection and dissemination in the human host. These findings could provide potential drug targets to combat the early stage of DENV infection.
MeSH term(s)	Humans ; Langerhans Cells/virology ; Langerhans Cells/immunology ; Lectins, C-Type/metabolism ; Dengue Virus/physiology ; Mannose-Binding Lectins/metabolism ; Dendritic Cells/virology ; Dendritic Cells/immunology ; Antigens, CD/metabolism ; Dengue/virology ; Dengue/immunology ; Cell Movement ; Cells, Cultured ; Skin/virology ; Skin/pathology ; Epidermis/virology ; Epidermis/pathology ; Epidermis/metabolism
Chemical Substances	Lectins, C-Type ; Mannose-Binding Lectins ; CD207 protein, human ; Antigens, CD
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2023.09.287
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Article ; Online: Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies.

Bermejo-Jambrina, Marta / van der Donk, Lieve Eh / van Hamme, John L / Wilflingseder, Doris / de Bree, Godelieve / Prins, Maria / de Jong, Menno / Nieuwkerk, Pythia / van Gils, Marit J / Kootstra, Neeltje A / Geijtenbeek, Teunis Bh

The EMBO journal

2024 Volume 43, Issue 7, Page(s) 1135–1163

Abstract: Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here, we uncover the role of the complement system in the ... ...

Abstract	Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here, we uncover the role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Antibodies, Viral ; Complement System Proteins ; Inflammation ; Immunity, Innate
Chemical Substances	Antibodies, Viral ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/s44318-024-00061-0
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Zs.A 1808: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 100: Show issues

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Article: Variations in the Abortive HIV-1 RNA Hairpin Do Not Impede Viral Sensing and Innate Immune Responses.

Stunnenberg, Melissa / van Hamme, John L / Das, Atze T / Berkhout, Ben / Geijtenbeek, Teunis B H

Pathogens (Basel, Switzerland)

2021 Volume 10, Issue 7

Abstract: The highly conserved trans-acting response element (TAR) present in the RNA genome of human immunodeficiency virus 1 (HIV-1) is a stably folded hairpin structure involved in viral replication. However, TAR is also sensed by viral sensors, leading to ... ...

Abstract	The highly conserved trans-acting response element (TAR) present in the RNA genome of human immunodeficiency virus 1 (HIV-1) is a stably folded hairpin structure involved in viral replication. However, TAR is also sensed by viral sensors, leading to antiviral immunity. While high variation in the TAR RNA structure renders the virus replication-incompetent, effects on viral sensing remain unclear. Here, we investigated the role of TAR RNA structure and stability on viral sensing. TAR mutants with deletions in the TAR hairpin that enhanced thermodynamic stability increased antiviral responses. Strikingly, TAR mutants with lower stability due to destabilization of the TAR hairpin also increased antiviral responses without affecting pro-inflammatory responses. Moreover, mutations that affected the TAR RNA sequence also enhanced specific antiviral responses. Our data suggest that mutations in TAR of replication-incompetent viruses can still induce immune responses via viral sensors, hereby underscoring the robustness of HIV-1 RNA sensing mechanisms.
Language	English
Publishing date	2021-07-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens10070897
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Article ; Online: Abortive HIV-1 RNA induces pro-IL-1β maturation via protein kinase PKR and inflammasome activation in humans.

Stunnenberg, Melissa / van Hamme, John L / Trimp, Marjolein / Gringhuis, Sonja I / Geijtenbeek, Teunis B H

European journal of immunology

2021 Volume 51, Issue 10, Page(s) 2464–2477

Abstract: The proinflammatory cytokine IL-1β mediates high levels of immune activation observed during acute and chronic human immunodeficiency virus 1 (HIV-1) infection. Little is known about the mechanisms that drive IL-1β activation during HIV-1 infection. Here, ...

Abstract	The proinflammatory cytokine IL-1β mediates high levels of immune activation observed during acute and chronic human immunodeficiency virus 1 (HIV-1) infection. Little is known about the mechanisms that drive IL-1β activation during HIV-1 infection. Here, we have identified a crucial role for abortive HIV-1 RNAs in inducing IL-1β in humans. Abortive HIV-1 RNAs were sensed by protein kinase RNA-activated (PKR), which triggered activation of the canonical NLRP3 inflammasome and caspase-1, leading to pro-IL-1β processing and secretion. PKR activated the inflammasome via ROS generation and MAP kinases ERK1/2, JNK, and p38. Inhibition of PKR during HIV-1 infection blocked IL-1β production. As abortive HIV-1 RNAs are produced during productive infection and latency, our data strongly suggest that targeting PKR signaling might attenuate immune activation during acute and chronic HIV-1 infection.
MeSH term(s)	HIV Infections/metabolism ; HIV Infections/virology ; HIV-1/physiology ; Host-Pathogen Interactions ; Humans ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; MAP Kinase Signaling System ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Pattern Recognition/metabolism ; Signal Transduction ; eIF-2 Kinase/metabolism
Chemical Substances	IL1B protein, human ; Inflammasomes ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein ; RNA, Viral ; Reactive Oxygen Species ; Receptors, Pattern Recognition ; EIF2AK2 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2021-07-23
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149275
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 85: Show issues

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Article ; Online: Crosstalk between R848 and abortive HIV-1 RNA-induced signaling enhances antiviral immunity.

Stunnenberg, Melissa / van Hamme, John L / Zijlstra-Willems, Esther M / Gringhuis, Sonja I / Geijtenbeek, Teunis B H

Journal of leukocyte biology

2022 Volume 112, Issue 2, Page(s) 289–298

Abstract: Pathogens trigger multiple pattern recognition receptors (PRRs) that together dictate innate and adaptive immune responses. Understanding the crosstalk between PRRs is important to enhance vaccine efficacy. Abortive HIV-1 RNA transcripts are produced ... ...

Abstract	Pathogens trigger multiple pattern recognition receptors (PRRs) that together dictate innate and adaptive immune responses. Understanding the crosstalk between PRRs is important to enhance vaccine efficacy. Abortive HIV-1 RNA transcripts are produced during acute and chronic HIV-1 infection and are known ligands for different PRRs, leading to antiviral and proinflammatory responses. Here, we have investigated the crosstalk between responses induced by these 58 nucleotide-long HIV-1 RNA transcripts and different TLR ligands. Costimulation of dendritic cells (DCs) with abortive HIV-1 RNA and TLR7/8 agonist R848, but not other TLR agonists, resulted in enhanced antiviral type I IFN responses as well as adaptive immune responses via the induction of DC-mediated T helper 1 (T
MeSH term(s)	Adjuvants, Immunologic ; Antiviral Agents ; CD8-Positive T-Lymphocytes ; Dendritic Cells ; HIV-1/physiology ; Immunity, Innate ; RNA ; Receptors, Pattern Recognition
Chemical Substances	Adjuvants, Immunologic ; Antiviral Agents ; Receptors, Pattern Recognition ; RNA (63231-63-0)
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.4A0721-365R
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Zs.A 603: Show issues

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Article ; Online: Prevotella timonensis bacteria associated with vaginal dysbiosis enhance HIV-1 susceptibility of vaginal CD4+ T cells.

van Teijlingen, Nienke H / van Smoorenburg, Marleen Y / Sarrami-Forooshani, Ramin / Zijlstra-Willems, Esther M / van Hamme, John L / Borgdorff, Hanneke / van de Wijgert, Janneke Hhm / van Leeuwen, Elisabeth / van der Post, Joris A M / Strijbis, Karin / Ribeiro, Carla M S / Geijtenbeek, Teunis B H

The Journal of infectious diseases

2024

Abstract: Dysbiosis of the vaginal microbiome poses a serious risk for sexual HIV-1 transmission. Prevotella spp. are abundant during vaginal dysbiosis and associated with enhanced HIV-1 susceptibility; however, underlying mechanisms remain unclear. Here, we ... ...

Abstract	Dysbiosis of the vaginal microbiome poses a serious risk for sexual HIV-1 transmission. Prevotella spp. are abundant during vaginal dysbiosis and associated with enhanced HIV-1 susceptibility; however, underlying mechanisms remain unclear. Here, we investigated the direct effect of vaginal bacteria on HIV-1 susceptibility of vaginal CD4+ T cells. Notably, pre-exposure to Prevotella timonensis enhanced HIV-1 uptake by vaginal T cells, leading to increased viral fusion and enhanced virus production. Pre-exposure to antiretroviral inhibitors abolished Prevotella timonensis-enhanced infection. Hence, our study shows that the vaginal microbiome directly affects mucosal CD4+ T cell susceptibility, emphasising importance of vaginal dysbiosis diagnosis and treatment.
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiae166
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Uh II Zs.50: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 445: Show issues

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Article: Variations in the Abortive HIV-1 RNA Hairpin Do Not Impede Viral Sensing and Innate Immune Responses

Stunnenberg, Melissa / van Hamme, John L. / Das, Atze T. / Berkhout, Ben / Geijtenbeek, Teunis B. H.

Pathogens. 2021 July 15, v. 10, no. 7

2021

Abstract	The highly conserved trans-acting response element (TAR) present in the RNA genome of human immunodeficiency virus 1 (HIV-1) is a stably folded hairpin structure involved in viral replication. However, TAR is also sensed by viral sensors, leading to antiviral immunity. While high variation in the TAR RNA structure renders the virus replication-incompetent, effects on viral sensing remain unclear. Here, we investigated the role of TAR RNA structure and stability on viral sensing. TAR mutants with deletions in the TAR hairpin that enhanced thermodynamic stability increased antiviral responses. Strikingly, TAR mutants with lower stability due to destabilization of the TAR hairpin also increased antiviral responses without affecting pro-inflammatory responses. Moreover, mutations that affected the TAR RNA sequence also enhanced specific antiviral responses. Our data suggest that mutations in TAR of replication-incompetent viruses can still induce immune responses via viral sensors, hereby underscoring the robustness of HIV-1 RNA sensing mechanisms.
Keywords	Human immunodeficiency virus 1 ; RNA ; genome ; nucleotide sequences ; thermodynamics ; virus replication ; viruses
Language	English
Dates of publication	2021-0715
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens10070897
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: SARS-CoV-2 suppresses TLR4-induced immunity by dendritic cells via C-type lectin receptor DC-SIGN.

van der Donk, Lieve E H / Bermejo-Jambrina, Marta / van Hamme, John L / Volkers, Mette M W / van Nuenen, Ad C / Kootstra, Neeltje A / Geijtenbeek, Teunis B H

PLoS pathogens

2023 Volume 19, Issue 10, Page(s) e1011735

Abstract: SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with ...

Abstract	SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.
MeSH term(s)	Humans ; SARS-CoV-2/metabolism ; Toll-Like Receptor 4/metabolism ; Lipopolysaccharides/pharmacology ; Lipopolysaccharides/metabolism ; Superinfection ; COVID-19/metabolism ; Lectins, C-Type/metabolism ; Cytokines/metabolism ; Dendritic Cells
Chemical Substances	DC-specific ICAM-3 grabbing nonintegrin ; spike protein, SARS-CoV-2 ; Toll-Like Receptor 4 ; Lipopolysaccharides ; Lectins, C-Type ; Cytokines ; TLR4 protein, human
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011735
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Article ; Online: Ectopic expression of cGAS in

Waanders, Lisette / van der Donk, Lieve E H / Ates, Louis S / Maaskant, Janneke / van Hamme, John L / Eldering, Eric / van Bruggen, Jaco A C / Rietveld, Joanne M / Bitter, Wilbert / Geijtenbeek, Teunis B H / Kuijl, Coenraad P

Journal for immunotherapy of cancer

2023 Volume 11, Issue 4

Abstract: Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with ... ...

Abstract	Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with phosphodiester linkages 2'-5' and 3'-5' (cGAMPs), that are produced by cyclic GMP-AMP synthetase (cGAS). However, delivery of STING pathway agonists to the tumor site is a challenge. Bacterial vaccine strains have the ability to specifically colonize hypoxic tumor tissues and could therefore be modified to overcome this challenge. Combining high STING-mediated IFN-β levels with the immunostimulatory properties of Methods: We have engineered Results: Expression of cGAS in Conclusion: S. typhimurium
MeSH term(s)	Humans ; Salmonella typhimurium/metabolism ; Ectopic Gene Expression ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Macrophages/metabolism ; Interferon Type I ; Neoplasms/metabolism ; Dendritic Cells/metabolism ; Tumor Microenvironment
Chemical Substances	cyclic guanosine monophosphate-adenosine monophosphate ; Nucleotidyltransferases (EC 2.7.7.-) ; Interferon Type I
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005839
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Article ; Online: Low energy nebulization preserves integrity of SARS-CoV-2 mRNA vaccines for respiratory delivery.

van Rijn, Cees J M / Vlaming, Killian E / Bem, Reinout A / Dekker, Rob J / Poortinga, Albert / Breit, Timo / van Leeuwen, Selina / Ensink, Wim A / van Wijnbergen, Kelly / van Hamme, John L / Bonn, Daniel / Geijtenbeek, Teunis B H

Scientific reports

2023 Volume 13, Issue 1, Page(s) 8851

Abstract: Nebulization of mRNA therapeutics can be used to directly target the respiratory tract. A promising prospect is that mucosal administration of lipid nanoparticle (LNP)-based mRNA vaccines may lead to a more efficient protection against respiratory ... ...

Abstract	Nebulization of mRNA therapeutics can be used to directly target the respiratory tract. A promising prospect is that mucosal administration of lipid nanoparticle (LNP)-based mRNA vaccines may lead to a more efficient protection against respiratory viruses. However, the nebulization process can rupture the LNP vehicles and degrade the mRNA molecules inside. Here we present a novel nebulization method able to preserve substantially the integrity of vaccines, as tested with two SARS-CoV-2 mRNA vaccines. We compare the new method with well-known nebulization methods used for medical respiratory applications. We find that a lower energy level in generating LNP droplets using the new nebulization method helps safeguard the integrity of the LNP and vaccine. By comparing nebulization techniques with different energy dissipation levels we find that LNPs and mRNAs can be kept largely intact if the energy dissipation remains below a threshold value, for LNP integrity 5-10 J/g and for mRNA integrity 10-20 J/g for both vaccines.
MeSH term(s)	Humans ; COVID-19 Vaccines ; SARS-CoV-2/genetics ; COVID-19/prevention & control ; RNA, Messenger/genetics ; mRNA Vaccines ; Nanoparticles
Chemical Substances	COVID-19 Vaccines ; RNA, Messenger ; mRNA Vaccines
Language	English
Publishing date	2023-05-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-35872-4
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