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Artikel ; Online: Sequential Early-Life Infections Alter Peripheral Blood Transcriptomics in Aging Female Mice but Not the Response to De Novo Infection with Influenza Virus or M. tuberculosis.

Lanzer, Kathleen G / Cookenham, Tres / Lehrmann, Elin / Zhang, Yongqing / Duso, Debbie / Xie, Qingqing / Reiley, William W / Becker, Kevin G / Blackman, Marcia A

ImmunoHorizons

2023 Band 7, Heft 8, Seite(n) 562–576

Abstract: To determine the impact of accumulating Ag exposure on immunity in the aging mouse, and to develop a model more relevant to humans who are exposed to multiple pathogens during life, we sequentially infected young female mice with four distinct pathogens ... ...

Abstract	To determine the impact of accumulating Ag exposure on immunity in the aging mouse, and to develop a model more relevant to humans who are exposed to multiple pathogens during life, we sequentially infected young female mice with four distinct pathogens at 8-wk intervals: murine γ-herpesvirus 68, Sendai virus, murine CMV, and Heligmosomoides polygyrus. Mock-infected mice received PBS. After aging the sequentially infected and mock-infected mice to 18-25 mo under specific pathogen-free conditions, we analyzed multiple immune parameters. We assessed transcriptional activity in peripheral blood, T cell phenotype, the diversity of influenza epitopes recognized by CD8 T cells, and the response of the animals to infection with influenza virus and Mycobacterium tuberculosis. Our data show enhanced transcriptional activation in sequentially infected aged mice, with changes in some CD8 T cell subsets. However, there was no measurable difference in the response of mock-infected and sequentially infected aged mice to de novo infection with either influenza virus or M. tuberculosis at 18-21 mo. Unexpectedly, a single experiment in which 25-mo-old female mice were challenged with influenza virus revealed a significantly higher survival rate for sequentially infected (80%) versus mock-infected (20%) mice. These data suggest that although exposure to a variety of pathogen challenges in the mouse model does not overtly impact cellular markers of immunity in aged female mice following de novo respiratory infection, subtle changes may emerge in other compartments or with increasing age.
Mesh-Begriff(e)	Animals ; Female ; Mice ; Aging ; Mycobacterium tuberculosis ; Orthomyxoviridae ; Transcriptome ; Tuberculosis
Sprache	Englisch
Erscheinungsdatum	2023-08-09
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ISSN	2573-7732
ISSN (online)	2573-7732
DOI	10.4049/immunohorizons.2200066
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Visualization of Resident Memory CD8 T Cells in the Lungs of Young and Aged Influenza Memory Mice and after Heterosubtypic Challenge.

Cookenham, Tres / Lanzer, Kathleen G / Tighe, Mike / Ward, Jerrold M / Reiley, William W / Blackman, Marcia A

ImmunoHorizons

2021 Band 5, Heft 7, Seite(n) 543–556

Abstract: Memory T cells that are resident in the tissues (T resident memory [Trm]) serve as frontline responders to prevent reinfection by pathogens. Trm in the lung protect against respiratory viruses. Although these cells have been well characterized, little is ...

Abstract	Memory T cells that are resident in the tissues (T resident memory [Trm]) serve as frontline responders to prevent reinfection by pathogens. Trm in the lung protect against respiratory viruses. Although these cells have been well characterized, little is known about the impact of immune aging on the establishment, maintenance, function and recall of lung-resident Trm in the context of an influenza virus infection. Aging is associated with a progressive decline in immune function and a generalized inflammatory syndrome, referred to as inflammaging. In this study, we analyzed inflammation in the lung and assessed numbers and function of lung Trm after primary influenza infection and heterosubtypic challenge of young and aged mice. Our analysis showed that aged mice had more severe and sustained lung inflammation than young mice. Analysis of Trm numbers by flow cytometry and direct imaging showed comparable or higher numbers of Trm in aged compared with young mice, with a similar rate of decline over time in both groups of mice. Furthermore, influenza virus-specific Trm from young and aged memory mice were both functional in vitro, and the mice were protected from heterosubtypic challenge. Finally, there were enhanced numbers of T cells resident in the lungs of aged compared with young mice after heterosubtypic viral challenge. The data suggest that the generation, maintenance, and function of Trm in aged mice are not severely impaired and the increased numbers in aged compared with young mice after heterosubtypic challenge may be associated with enhanced lung inflammation in the aged mice.
Mesh-Begriff(e)	Aged ; Aging/immunology ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Cross Protection/immunology ; Disease Models, Animal ; Female ; Humans ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza A Virus, H3N2 Subtype/immunology ; Influenza, Human/immunology ; Influenza, Human/pathology ; Influenza, Human/virology ; Lung/cytology ; Lung/immunology ; Memory T Cells/immunology ; Mice ; Young Adult
Sprache	Englisch
Erscheinungsdatum	2021-07-15
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2573-7732
ISSN (online)	2573-7732
DOI	10.4049/immunohorizons.2100032
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Correction to: Virtual memory cells make a major contribution to the response of aged influenza-naïve mice to influenza virus infection.

Lanzer, Kathleen G / Cookenham, Tres / Reiley, William W / Blackman, Marcia A

Immunity & ageing : I & A

2018 Band 15, Seite(n) 18

Abstract: This corrects the article DOI: 10.1186/s12979-018-0122-y.]. ...

Abstract	[This corrects the article DOI: 10.1186/s12979-018-0122-y.].
Sprache	Englisch
Erscheinungsdatum	2018-08-21
Erscheinungsland	England
Dokumenttyp	Journal Article ; Published Erratum
ZDB-ID	2168941-6
ISSN	1742-4933
ISSN	1742-4933
DOI	10.1186/s12979-018-0123-x
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Virtual memory cells make a major contribution to the response of aged influenza-naïve mice to influenza virus infection.

Lanzer, Kathleen G / Cookenham, Tres / Reiley, William W / Blackman, Marcia A

Immunity & ageing : I & A

2018 Band 15, Seite(n) 17

Abstract: Background: A diverse repertoire of naïve T cells is thought to be essential for a robust response to new infections. However, a key aspect of aging of the T cell compartment is a decline in numbers and diversity of peripheral naïve T cells. We have ... ...

Abstract	Background: A diverse repertoire of naïve T cells is thought to be essential for a robust response to new infections. However, a key aspect of aging of the T cell compartment is a decline in numbers and diversity of peripheral naïve T cells. We have hypothesized that the age-related decline in naïve T cells forces the immune system to respond to new infections using cross-reactive memory T cells generated to previous infections that dominate the aged peripheral T cell repertoire. Results: Here we confirm that the CD8 T cell response of aged, influenza-naïve mice to primary infection with influenza virus is dominated by T cells that derive from the memory T cell pool. These cells exhibit the phenotypic characteristics of virtual memory cells rather than true memory cells. Furthermore, we find that the repertoire of responding CD8 T cells is constrained compared with that of young mice, and differs significantly between individual aged mice. After infection, these virtual memory CD8 T cells effectively develop into granzyme-producing effector cells, and clear virus with kinetics comparable to naïve CD8 T cells from young mice. Conclusions: The response of aged, influenza-naive mice to a new influenza infection is mediated largely by memory CD8 T cells. However, unexpectedly, they have the phenotype of VM cells. In response to de novo influenza virus infection, the VM cells develop into granzyme-producing effector cells and clear virus with comparable kinetics to young CD8 T cells.
Sprache	Englisch
Erscheinungsdatum	2018-08-08
Erscheinungsland	England
Dokumenttyp	Journal Article
ZDB-ID	2168941-6
ISSN	1742-4933
ISSN	1742-4933
DOI	10.1186/s12979-018-0122-y
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity.

Roche, Kathryn L / Remiszewski, Stacy / Todd, Matthew J / Kulp, John L / Tang, Liudi / Welsh, Alison V / Barry, Ashley P / De, Chandrav / Reiley, William W / Wahl, Angela / Garcia, J Victor / Luftig, Micah A / Shenk, Thomas / Tonra, James R / Murphy, Eain A / Chiang, Lillian W

The Journal of clinical investigation

2023 Band 133, Heft 12

Abstract: Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity ... ...

Abstract	Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.
Mesh-Begriff(e)	Animals ; Mice ; Antiviral Agents/pharmacology ; Sirtuin 2/genetics ; Coronavirus ; Coronavirus Infections ; RNA, Viral
Chemische Substanzen	Antiviral Agents ; Sirtuin 2 (EC 3.5.1.-) ; RNA, Viral
Sprache	Englisch
Erscheinungsdatum	2023-06-15
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI158978
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Vaccination of aged mice with adjuvanted recombinant influenza nucleoprotein enhances protective immunity

Cookenham, Tres / Lanzer, Kathleen G / Gage, Emily / Lorenzo, Erica C / Carter, Darrick / Coler, Rhea N / Baldwin, Susan L / Haynes, Laura / Reiley, William W / Blackman, Marcia A

Vaccine. 2020 July 14, v. 38, no. 33

2020

Abstract: Elderly individuals are highly susceptible to influenza virus (IAV) infection and respond poorly to influenza vaccines. Although the generally accepted correlate of protection following influenza vaccination is neutralizing antibody titers, cytotoxic T ... ...

Abstract	Elderly individuals are highly susceptible to influenza virus (IAV) infection and respond poorly to influenza vaccines. Although the generally accepted correlate of protection following influenza vaccination is neutralizing antibody titers, cytotoxic T cell activity has been found to be a better correlate in the elderly. This suggests that vaccines designed to protect against influenza in the elderly should induce both humoral and cellular immunity. The co-induction of T cell immunity is additionally advantageous, as virus-specific T cells are frequently cross-reactive against different strains of IAV. Here, we tested the capacity of a synthetic TLR-4 adjuvant, SLA-SE (second-generation lipid adjuvant formulated in a squalene-based oil-in-water emulsion) to elicit T cell immunity to a recombinant influenza nucleoprotein (rNP), in both young and aged mice. IAV challenge of vaccinated mice resulted in a modest increase in the numbers of NP-specific CD4 and CD8 effector T cells in the spleen, but did not increase numbers of memory phenotype CD8 T cells generated following viral clearance (compared to control vaccinated mice). Cytotoxic activity of CD8, but not CD4 T cells was increased. In addition, SLA-SE adjuvanted vaccination specifically enhanced the production of NP-specific IgG2c antibodies in both young and aged mice. Although NP-specific antibodies are not neutralizing, they can cooperate with CD8 T cells and antigen-presenting cells to enhance protective immunity. Importantly, SLA-SE adjuvanted rNP-vaccination of aged mice resulted in significantly enhanced viral clearance. In addition, vaccination of aged mice resulted in enhanced survival after lethal challenge compared to control vaccination, that approached statistical significance. These data demonstrate the potential of SLA-SE adjuvanted rNP vaccines to (i) generate both cellular and humoral immunity to relatively conserved IAV proteins and (ii) elicit protective immunity to IAV in aged mice.
Schlagwörter	Orthomyxoviridae ; adjuvants ; cell-mediated immunity ; cytotoxicity ; elderly ; emulsions ; humoral immunity ; influenza ; influenza vaccination ; lipids ; memory ; nucleoproteins ; phenotype ; spleen
Sprache	Englisch
Erscheinungsverlauf	2020-0714
Umfang	p. 5256-5267.
Erscheinungsort	Elsevier Ltd
Dokumenttyp	Artikel
Anmerkung	NAL-AP-2-clean
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2020.05.085
Datenquelle	NAL Katalog (AGRICOLA)

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Artikel ; Online: Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19

bioRxiv

Abstract: Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a limited range of other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad range of ... ...

Abstract	Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a limited range of other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad range of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2024-04-29
Verlag	Cold Spring Harbor Laboratory
Dokumenttyp	Artikel ; Online
DOI	10.1101/2024.04.26.591329
Datenquelle	COVID19

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Artikel: Comparative Safety and Efficacy Profile of a Novel Oil in Water Vaccine Adjuvant Comprising Vitamins A and E and a Catechin in Protective Anti-Influenza Immunity

Patel, Sapna / Faraj, Yasser / Duso, Debra K / Reiley, William W / Karlsson, Erik A / Schultz-Cherry, Stacey / Vajdy, Michael

Nutrients. 2017 May 21, v. 9, no. 5

2017

Abstract: Non-replicating vaccines, such as those based on recombinant proteins, require adjuvants and delivery systems, which have thus far depended on mimicking pathogen danger signals and strong pro-inflammatory responses. In search of a safer and more ... ...

Abstract	Non-replicating vaccines, such as those based on recombinant proteins, require adjuvants and delivery systems, which have thus far depended on mimicking pathogen danger signals and strong pro-inflammatory responses. In search of a safer and more efficacious alternative, we tested whether vaccinations with influenza recombinant hemagglutinin (HA) mixed with a novel vegetable oil in water emulsion adjuvant (Natural Immune-enhancing Delivery System, NIDS), based on the immune-enhancing synergy of vitamins A and E and a catechin, could protect against intra-nasal challenge with live influenza virus. Vaccinations of inbred Brag Albino strain c (BALB/c) mice, with HA mixed with NIDS compared to other adjuvants, i.e., a squalene oil in water emulsion (Sq. oil), and the Toll Like Receptor 3 (TLR3) agonist Poly (I:C), induced significantly lower select innate pro-inflammatory responses in serum, but induced significantly higher adaptive antibody and splenic T Helper 1 (TH1) or TH2, but not TH17, responses. Vaccinations with NIDS protected against infection, as measured by clinical scores, lung viral loads, and serum hemagglutination inhibition titers. The NIDS exhibited a strong dose sparing effect and the adjuvant action of NIDS was intact in the outbred CD1 mice. Importantly, vaccinations with the Sq. oil, but not NIDS, induced a significantly higher Serum Amyloid P component, an acute phase reactant secreted by hepatocytes, and total serum IgE. Thus, the NIDS may be used as a clinically safer and more efficacious vaccine adjuvant against influenza, and potentially other infectious diseases.
Schlagwörter	CD4-positive T-lymphocytes ; Orthomyxoviridae ; Toll-like receptor 3 ; acute phase proteins ; agonists ; albino ; amyloid ; antibodies ; blood serum ; catechin ; emulsions ; hemagglutination ; hemagglutinins ; hepatocytes ; immunoglobulin E ; inflammation ; influenza ; lungs ; mice ; pathogens ; recombinant proteins ; squalene ; vaccination ; vaccine adjuvants ; vaccines ; vegetable oil ; viral load ; vitamin A
Sprache	Englisch
Erscheinungsverlauf	2017-0521
Erscheinungsort	Multidisciplinary Digital Publishing Institute
Dokumenttyp	Artikel
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu9050516
Datenquelle	NAL Katalog (AGRICOLA)

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Artikel ; Online: Vaccination of aged mice with adjuvanted recombinant influenza nucleoprotein enhances protective immunity.

Cookenham, Tres / Lanzer, Kathleen G / Gage, Emily / Lorenzo, Erica C / Carter, Darrick / Coler, Rhea N / Baldwin, Susan L / Haynes, Laura / Reiley, William W / Blackman, Marcia A

Vaccine

2020 Band 38, Heft 33, Seite(n) 5256–5267

Abstract	Elderly individuals are highly susceptible to influenza virus (IAV) infection and respond poorly to influenza vaccines. Although the generally accepted correlate of protection following influenza vaccination is neutralizing antibody titers, cytotoxic T cell activity has been found to be a better correlate in the elderly. This suggests that vaccines designed to protect against influenza in the elderly should induce both humoral and cellular immunity. The co-induction of T cell immunity is additionally advantageous, as virus-specific T cells are frequently cross-reactive against different strains of IAV. Here, we tested the capacity of a synthetic TLR-4 adjuvant, SLA-SE (second-generation lipid adjuvant formulated in a squalene-based oil-in-water emulsion) to elicit T cell immunity to a recombinant influenza nucleoprotein (rNP), in both young and aged mice. IAV challenge of vaccinated mice resulted in a modest increase in the numbers of NP-specific CD4 and CD8 effector T cells in the spleen, but did not increase numbers of memory phenotype CD8 T cells generated following viral clearance (compared to control vaccinated mice). Cytotoxic activity of CD8, but not CD4 T cells was increased. In addition, SLA-SE adjuvanted vaccination specifically enhanced the production of NP-specific IgG2c antibodies in both young and aged mice. Although NP-specific antibodies are not neutralizing, they can cooperate with CD8 T cells and antigen-presenting cells to enhance protective immunity. Importantly, SLA-SE adjuvanted rNP-vaccination of aged mice resulted in significantly enhanced viral clearance. In addition, vaccination of aged mice resulted in enhanced survival after lethal challenge compared to control vaccination, that approached statistical significance. These data demonstrate the potential of SLA-SE adjuvanted rNP vaccines to (i) generate both cellular and humoral immunity to relatively conserved IAV proteins and (ii) elicit protective immunity to IAV in aged mice.
Mesh-Begriff(e)	Animals ; Antibodies, Viral ; CD8-Positive T-Lymphocytes ; Influenza Vaccines ; Influenza, Human/prevention & control ; Mice ; Mice, Inbred BALB C ; Nucleoproteins ; Orthomyxoviridae Infections/prevention & control ; Vaccination
Chemische Substanzen	Antibodies, Viral ; Influenza Vaccines ; Nucleoproteins
Sprache	Englisch
Erscheinungsdatum	2020-06-12
Erscheinungsland	Netherlands
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2020.05.085
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Comparative Safety and Efficacy Profile of a Novel Oil in Water Vaccine Adjuvant Comprising Vitamins A and E and a Catechin in Protective Anti-Influenza Immunity.

Patel, Sapna / Faraj, Yasser / Duso, Debra K / Reiley, William W / Karlsson, Erik A / Schultz-Cherry, Stacey / Vajdy, Michael

Nutrients

2017 Band 9, Heft 5

Abstract	Non-replicating vaccines, such as those based on recombinant proteins, require adjuvants and delivery systems, which have thus far depended on mimicking pathogen danger signals and strong pro-inflammatory responses. In search of a safer and more efficacious alternative, we tested whether vaccinations with influenza recombinant hemagglutinin (HA) mixed with a novel vegetable oil in water emulsion adjuvant (Natural Immune-enhancing Delivery System, NIDS), based on the immune-enhancing synergy of vitamins A and E and a catechin, could protect against intra-nasal challenge with live influenza virus. Vaccinations of inbred Brag Albino strain c (BALB/c) mice, with HA mixed with NIDS compared to other adjuvants, i.e., a squalene oil in water emulsion (Sq. oil), and the Toll Like Receptor 3 (TLR3) agonist Poly (I:C), induced significantly lower select innate pro-inflammatory responses in serum, but induced significantly higher adaptive antibody and splenic T Helper 1 (TH1) or TH2, but not TH17, responses. Vaccinations with NIDS protected against infection, as measured by clinical scores, lung viral loads, and serum hemagglutination inhibition titers. The NIDS exhibited a strong dose sparing effect and the adjuvant action of NIDS was intact in the outbred CD1 mice. Importantly, vaccinations with the Sq. oil, but not NIDS, induced a significantly higher Serum Amyloid P component, an acute phase reactant secreted by hepatocytes, and total serum IgE. Thus, the NIDS may be used as a clinically safer and more efficacious vaccine adjuvant against influenza, and potentially other infectious diseases.
Sprache	Englisch
Erscheinungsdatum	2017-05-21
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu9050516
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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