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Article: High Frequencies of Antiviral Effector Memory T

Dhanushkodi, Nisha Rajeswari / Prakash, Swayam / Quadiri, Afshana / Zayou, Latifa / Singer, Mahmoud / Takashi, Nakayama / Vahed, Hawa / BenMohamed, Lbachir

bioRxiv : the preprint server for biology

2023

Abstract: Vaginal mucosa-resident anti-viral effector memory B- and T cells appeared to play a crucial role in protection against genital herpes. However, how to mobilize such protective immune cells into the vaginal tissue close to infected epithelial cells ... ...

Abstract	Vaginal mucosa-resident anti-viral effector memory B- and T cells appeared to play a crucial role in protection against genital herpes. However, how to mobilize such protective immune cells into the vaginal tissue close to infected epithelial cells remains to be determined. In the present study, we investigate whether and how, CCL28, a major mucosal-associated chemokine, mobilizes effector memory B- and T cells in leading to protecting mucosal surfaces from herpes infection and disease. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). We found the presence of significant frequencies of HSV-specific memory CCR10
Language	English
Publishing date	2023-05-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.23.542021
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Article ; Online: Therapeutic prime/pull vaccination of HSV-2-infected guinea pigs with the ribonucleotide reductase 2 (RR2) protein and CXCL11 chemokine boosts antiviral local tissue-resident and effector memory CD4

Quadiri, Afshana / Prakash, Swayam / Dhanushkodi, Nisha Rajeswari / Singer, Mahmoud / Zayou, Latifa / Shaik, Amin Mohammed / Sun, Miyo / Suzer, Berfin / Lau, Lauren Su Lin / Chilukurri, Amruth / Vahed, Hawa / Schaefer, Hubert / BenMohamed, Lbachir

Journal of virology

2024 , Page(s) e0159623

Abstract: Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes an asymptomatic latent infection of sensory neurons of dorsal root ganglia (DRG). Chemical and physical stress cause intermittent virus reactivation from latently infected ...

Abstract	Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes an asymptomatic latent infection of sensory neurons of dorsal root ganglia (DRG). Chemical and physical stress cause intermittent virus reactivation from latently infected DRG and recurrent virus shedding in the genital mucosal epithelium causing genital herpes in symptomatic patients. While T cells appear to play a role in controlling virus reactivation from DRG and reducing the severity of recurrent genital herpes, the mechanisms for recruiting these T cells into DRG and the vaginal mucosa (VM) remain to be fully elucidated. The present study investigates the effect of CXCL9, CXCL10, and CXCL11 T-cell-attracting chemokines on the frequency and function of DRG- and VM-resident CD4
Language	English
Publishing date	2024-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01596-23
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Article: High Frequencies of Phenotypically and Functionally Senescent and Exhausted CD56

Srivastava, Ruchi / Dhanushkodi, Nisha / Prakash, Swayam / Coulon, Pierre Gregoire / Vahed, Hawa / Zayou, Latifa / Quadiri, Afshana / BenMohamed, Lbachir

bioRxiv : the preprint server for biology

2022

Abstract: Unvaccinated COVID-19 patients display a large spectrum of symptoms, ranging from asymptomatic to severe symptoms, the latter even causing death. Distinct Natural killer (NK) and ... ...

Abstract	Unvaccinated COVID-19 patients display a large spectrum of symptoms, ranging from asymptomatic to severe symptoms, the latter even causing death. Distinct Natural killer (NK) and CD4
Language	English
Publishing date	2022-07-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.07.26.501655
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Article ; Online: HDAC4 Mediates Smoking-Induced Pancreatic Cancer Metastasis.

Yang, Jiyong / Chheda, Chintan / Lim, Adrian / Hauptschein, Dina / Zayou, Latifa / Tang, Josiah / Pandol, Stephen J / Edderkaoui, Mouad

Pancreas

2022 Volume 51, Issue 2, Page(s) 190–195

Abstract: Objective: Cigarette smoking is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). In this project, we investigated the effect of smoking and the role of histone deacetylase 4 (HDAC4) in PDAC invasion and metastasis.: Methods: ... ...

Abstract	Objective: Cigarette smoking is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). In this project, we investigated the effect of smoking and the role of histone deacetylase 4 (HDAC4) in PDAC invasion and metastasis. Methods: Cells were treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and cigarette smoke extract and the mRNA levels of HDACs were measured by real-time polymerase chain reaction. Invasion was measured using the Matrigel Invasion Assay. Syngeneic PDAC mice were treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and metastasis measured. Human PDAC primary and metastatic tissues were analyzed by immunohistochemistry. Results: Levels of HDAC4 mRNA were increased by smoking. Smoking compounds significantly promoted invasion of cancer cells and promoted metastasis of PDAC cells to different organs, including the liver and the lung, whereas inhibition of HDAC4 prevented this effect. The effect of HDAC4 inhibition on preventing smoking-induced metastasis was greater in the liver compared with the lung. We found that HDAC4 is highly expressed in primary and metastatic PDAC tumors. Conclusions: We found that HDAC4 is the only HDAC induced by smoking among all HDACs analyzed. We found that smoking promotes invasion and metastasis of PDAC cells through a mechanism that involves HDAC4 and that HDAC4 is a promising target for preventing PDAC metastasis.
MeSH term(s)	Animals ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Histone Deacetylases/genetics ; Humans ; Mice ; Neoplasm Metastasis ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; RNA, Messenger ; Repressor Proteins/genetics ; Smoking/adverse effects ; Pancreatic Neoplasms
Chemical Substances	RNA, Messenger ; Repressor Proteins ; HDAC4 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2022-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	632831-3
ISSN	1536-4828 ; 0885-3177
ISSN (online)	1536-4828
ISSN	0885-3177
DOI	10.1097/MPA.0000000000001998
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Article ; Online: Antiviral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models.

Dhanushkodi, Nisha Rajeswari / Prakash, Swayam / Quadiri, Afshana / Zayou, Latifa / Srivastava, Ruchi / Shaik, Amin Mohammed / Suzer, Berfin / Ibraim, Izabela Coimbra / Landucci, Gary / Tifrea, Delia F / Singer, Mahmoud / Jamal, Leila / Edwards, Robert A / Vahed, Hawa / Brown, Lawrence / BenMohamed, Lbachir

Journal of immunology (Baltimore, Md. : 1950)

2024 Volume 212, Issue 4, Page(s) 576–585

Abstract: SARS-CoV-2 variants of concern (VOCs) continue to evolve and reemerge with chronic inflammatory long COVID sequelae, necessitating the development of anti-inflammatory therapeutic molecules. Therapeutic effects of the receptor for advanced glycation end ... ...

Abstract	SARS-CoV-2 variants of concern (VOCs) continue to evolve and reemerge with chronic inflammatory long COVID sequelae, necessitating the development of anti-inflammatory therapeutic molecules. Therapeutic effects of the receptor for advanced glycation end products (RAGE) were reported in many inflammatory diseases. However, a therapeutic effect of RAGE in COVID-19 has not been reported. In the present study, we investigated whether and how the RAGE-Ig fusion protein would have an antiviral and anti-inflammatory therapeutic effect in the COVID-19 system. The protective therapeutic effect of RAGE-Ig was determined in vivo in K18-hACE2 transgenic mice and Syrian golden hamsters infected with six VOCs of SARS-CoV-2. The underlying antiviral mechanism of RAGE-Ig was determined in vitro in SARS-CoV-2-infected human lung epithelial cells (BEAS-2B). Following treatment of K18-hACE2 mice and hamsters infected with various SARS-CoV-2 VOCs with RAGE-Ig, we demonstrated (1) significant dose-dependent protection (i.e., greater survival, less weight loss, lower virus replication in the lungs); (2) a reduction of inflammatory macrophages (F4/80+/Ly6C+) and neutrophils (CD11b+/Ly6G+) infiltrating the infected lungs; (3) a RAGE-Ig dose-dependent increase in the expression of type I IFNs (IFN-α and IFN-β) and type III IFN (IFNλ2) and a decrease in the inflammatory cytokines (IL-6 and IL-8) in SARS-CoV-2-infected human lung epithelial cells; and (4) a dose-dependent decrease in the expression of CD64 (FcgR1) on monocytes and lung epithelial cells from symptomatic COVID-19 patients. Our preclinical findings revealed type I and III IFN-mediated antiviral and anti-inflammatory therapeutic effects of RAGE-Ig protein against COVID-19 caused by multiple SARS-CoV-2 VOCs.
MeSH term(s)	Cricetinae ; Humans ; Mice ; Animals ; SARS-CoV-2 ; Mesocricetus ; COVID-19 ; Receptor for Advanced Glycation End Products/genetics ; Post-Acute COVID-19 Syndrome ; Mice, Transgenic ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Disease Models, Animal ; Lung ; gamma-Globulins ; Melphalan
Chemical Substances	Receptor for Advanced Glycation End Products ; K-18 conjugate ; Antiviral Agents ; gamma-Globulins ; Melphalan (Q41OR9510P)
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300392
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Article: Therapeutic Prime/Pull Vaccination of HSV-2 Infected Guinea Pigs with the Ribonucleotide Reductase 2 (RR2) Protein and CXCL11 Chemokine Boosts Antiviral Local Tissue-Resident and Effector Memory CD4

Quadiri, Afshana / Prakash, Swayam / Dhanushkodi, Nisha Rajeswari / Singer, Mahmoud / Zayou, Latifa / Shaik, Amin Mohammed / Sun, Miyo / Suzer, Berfin / Lau, Lauren / Chilukurri, Amruth / Vahed, Hawa / Schaefer, Hubert / BenMohamed, Lbachir

bioRxiv : the preprint server for biology

2023

Abstract: Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes latency in sensory neurons of the dorsal root ganglia (DRG). Intermittent virus reactivation from latency and shedding in the vaginal mucosa (VM) causes recurrent genital ... ...

Abstract	Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes latency in sensory neurons of the dorsal root ganglia (DRG). Intermittent virus reactivation from latency and shedding in the vaginal mucosa (VM) causes recurrent genital herpes. While T-cells appear to play a role in controlling virus reactivation and reducing the severity of recurrent genital herpes, the mechanisms for recruiting these T-cells into DRG and VM tissues remain to be fully elucidated. The present study investigates the effect of CXCL9, CXCL10, and CXCL11 T-cell-attracting chemokines on the frequency and function of DRG- and VM-resident CD4
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.08.552454
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A Broad-Spectrum Multi-Antigen mRNA/LNP-Based Pan-Coronavirus Vaccine Induced Potent Cross-Protective Immunity Against Infection and Disease Caused by Highly Pathogenic and Heavily Spike-Mutated SARS-CoV-2 Variants of Concern in the Syrian Hamster Model

Prakash, Swayam / Dhanushkodi, Nisha R / Singer, Mahmoud / Quadiri, Afshana / Zayou, Latifa / Vahed, Hawa / Coulon, Pierre-Gregoire / El Babsiri, Assia / Gil, Daniel / Ulmer, Jeffrey B / BENMOHAMED, LBACHIR

bioRxiv

Abstract: The first-generation Spike-alone-based COVID-19 vaccines have successfully contributed to reducing the risk of hospitalization, serious illness, and death caused by SARS-CoV-2 infections. However, waning immunity induced by these vaccines failed to ... ...

Abstract	The first-generation Spike-alone-based COVID-19 vaccines have successfully contributed to reducing the risk of hospitalization, serious illness, and death caused by SARS-CoV-2 infections. However, waning immunity induced by these vaccines failed to prevent immune escape by many variants of concern (VOCs) that emerged from 2020 to 2024, resulting in a prolonged COVID-19 pandemic. We hypothesize that a next-generation Coronavirus (CoV) vaccine incorporating highly conserved non-Spike SARS-CoV-2 antigens would confer stronger and broader cross-protective immunity against multiple VOCs. In the present study, we identified ten non-Spike antigens that are highly conserved in 8.7 million SARS-CoV-2 strains, twenty-one VOCs, SARS-CoV, MERS-CoV, Common Cold CoVs, and animal CoVs. Seven of the 10 antigens were preferentially recognized by CD8+ and CD4+ T-cells from unvaccinated asymptomatic COVID-19 patients, irrespective of VOC infection. Three out of the seven conserved non-Spike T cell antigens belong to the early expressed Replication and Transcription Complex (RTC) region, when administered to the golden Syrian hamsters, in combination with Spike, as nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP) (i.e., combined mRNA/LNP-based pan-CoV vaccine): (i) Induced high frequencies of lung-resident antigen-specific CXCR5+CD4+ T follicular helper (TFH) cells, GzmB+CD4+ and GzmB+CD8+ cytotoxic T cells (TCYT), and CD69+IFN-g+TNF-a+CD4+ and CD69+IFN-g+TNFa+CD8+ effector T cells (TEFF); and (ii) Reduced viral load and COVID-19-like symptoms caused by various VOCs, including the highly pathogenic B.1.617.2 Delta variant and the highly transmittable heavily Spike-mutated XBB1.5 Omicron sub-variant. The combined mRNA/LNP-based pan-CoV vaccine could be rapidly adapted for clinical use to confer broader cross-protective immunity against emerging highly mutated and pathogenic VOCs.
Keywords	covid19
Language	English
Publishing date	2024-02-15
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.02.14.580225
Database	COVID19

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Article: A Broad-Spectrum Multi-Antigen mRNA/LNP-Based Pan-Coronavirus Vaccine Induced Potent Cross-Protective Immunity Against Infection and Disease Caused by Highly Pathogenic and Heavily Spike-Mutated SARS-CoV-2 Variants of Concern in the Syrian Hamster Model.

bioRxiv : the preprint server for biology

2024

Abstract	The first-generation Spike-alone-based COVID-19 vaccines have successfully contributed to reducing the risk of hospitalization, serious illness, and death caused by SARS-CoV-2 infections. However, waning immunity induced by these vaccines failed to prevent immune escape by many variants of concern (VOCs) that emerged from 2020 to 2024, resulting in a prolonged COVID-19 pandemic. We hypothesize that a next-generation Coronavirus (CoV) vaccine incorporating highly conserved non-Spike SARS-CoV-2 antigens would confer stronger and broader cross-protective immunity against multiple VOCs. In the present study, we identified ten non-Spike antigens that are highly conserved in 8.7 million SARS-CoV-2 strains, twenty-one VOCs, SARS-CoV, MERS-CoV, Common Cold CoVs, and animal CoVs. Seven of the 10 antigens were preferentially recognized by CD8
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.14.580225
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Article ; Online: Cross-protection induced by highly conserved human B, CD4

Prakash, Swayam / Dhanushkodi, Nisha R / Zayou, Latifa / Ibraim, Izabela Coimbra / Quadiri, Afshana / Coulon, Pierre Gregoire / Tifrea, Delia F / Suzer, Berfin / Shaik, Amin Mohammed / Chilukuri, Amruth / Edwards, Robert A / Singer, Mahmoud / Vahed, Hawa / Nesburn, Anthony B / Kuppermann, Baruch D / Ulmer, Jeffrey B / Gil, Daniel / Jones, Trevor M / BenMohamed, Lbachir

Frontiers in immunology

2024 Volume 15, Page(s) 1328905

Abstract: Background: The coronavirus disease 2019 (COVID-19) pandemic has created one of the largest global health crises in almost a century. Although the current rate of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has decreased ... ...

Abstract	Background: The coronavirus disease 2019 (COVID-19) pandemic has created one of the largest global health crises in almost a century. Although the current rate of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has decreased significantly, the long-term outlook of COVID-19 remains a serious cause of morbidity and mortality worldwide, with the mortality rate still substantially surpassing even that recorded for influenza viruses. The continued emergence of SARS-CoV-2 variants of concern (VOCs), including multiple heavily mutated Omicron sub-variants, has prolonged the COVID-19 pandemic and underscores the urgent need for a next-generation vaccine that will protect from multiple SARS-CoV-2 VOCs. Methods: We designed a multi-epitope-based coronavirus vaccine that incorporated B, CD4 Results: The pan-variant SARS-CoV-2 vaccine (i) is safe , (ii) induces high frequencies of lung-resident functional CD8 Conclusion: A multi-epitope pan-variant SARS-CoV-2 vaccine bearing conserved human B- and T- cell epitopes from structural and non-structural SARS-CoV-2 antigens induced cross-protective immunity that facilitated virus clearance, and reduced morbidity, COVID-19-related lung pathology, and death caused by multiple SARS-CoV-2 VOCs.
MeSH term(s)	Animals ; Humans ; Mice ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; COVID-19/prevention & control ; COVID-19 Vaccines/immunology ; Epitopes, T-Lymphocyte/genetics ; Pandemics ; SARS-CoV-2/genetics ; Cross Protection
Chemical Substances	COVID-19 Vaccines ; Epitopes, T-Lymphocyte
Language	English
Publishing date	2024-01-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1328905
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Article ; Online: High frequencies of alpha common cold coronavirus/SARS-CoV-2 cross-reactive functional CD4

Coulon, Pierre-Gregoire / Prakash, Swayam / Dhanushkodi, Nisha R / Srivastava, Ruchi / Zayou, Latifa / Tifrea, Delia F / Edwards, Robert A / Figueroa, Cesar J / Schubl, Sebastian D / Hsieh, Lanny / Nesburn, Anthony B / Kuppermann, Baruch D / Bahraoui, Elmostafa / Vahed, Hawa / Gil, Daniel / Jones, Trevor M / Ulmer, Jeffrey B / BenMohamed, Lbachir

Frontiers in immunology

2024 Volume 15, Page(s) 1343716

Abstract: Background: Cross-reactive SARS-CoV-2-specific memory CD4: Methods: This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4: Results: Compared to severely ill COVID-19 patients and patients with ...

Abstract	Background: Cross-reactive SARS-CoV-2-specific memory CD4 Methods: This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4 Results: Compared to severely ill COVID-19 patients and patients with fatal COVID-19 outcomes, the asymptomatic COVID-19 patients displayed significantly: (i) higher rates of co-infection with the 229E alpha species of CCCs (α-CCC-229E); (ii) higher frequencies of cross-reactive functional CD134 Conclusions: These findings (i) support a crucial role of functional, poly-antigenic α-CCCs/SARS-CoV-2 cross-reactive memory CD4
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; CTLA-4 Antigen ; CD8-Positive T-Lymphocytes ; Common Cold ; Memory T Cells ; Hepatitis A Virus Cellular Receptor 2 ; Programmed Cell Death 1 Receptor ; CD4-Positive T-Lymphocytes ; Epitopes
Chemical Substances	CTLA-4 Antigen ; Hepatitis A Virus Cellular Receptor 2 ; Programmed Cell Death 1 Receptor ; Epitopes
Language	English
Publishing date	2024-03-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1343716
Database	MEDical Literature Analysis and Retrieval System OnLINE

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