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Article ; Online: A long-distance relationship: the commensal gut microbiota and systemic viruses.

Winkler, Emma S / Thackray, Larissa B

2019 Volume 37, Page(s) 44–51

Abstract: Recent advances defining the role of the commensal gut microbiota in the development, education, induction, function, and maintenance of the mammalian immune system inform our understanding of how immune responses govern the outcome of systemic virus ... ...

Abstract	Recent advances defining the role of the commensal gut microbiota in the development, education, induction, function, and maintenance of the mammalian immune system inform our understanding of how immune responses govern the outcome of systemic virus infection. While characterization of the impact of the local oral, respiratory, dermal and genitourinary microbiota on host immune responses and systemic virus infection is in its infancy, the gut microbiota interacts with host immunity systemically and at distal non-gastrointestinal tract sites to modulate the pathogenesis of systemic viruses. Gut microbes, microbe-associated molecular patterns, and microbe-derived metabolites engage receptors expressed on the cell surface, in the endosome, or in the cytoplasm to orchestrate optimal innate and adaptive immune responses important for controlling systemic virus infection.
MeSH term(s)	Adaptive Immunity ; Animals ; B-Lymphocytes/immunology ; Cytokines/metabolism ; Gastrointestinal Microbiome/immunology ; Gastrointestinal Tract/immunology ; Gastrointestinal Tract/microbiology ; Gastrointestinal Tract/virology ; Host Microbial Interactions/immunology ; Immunity, Innate ; Interferons/metabolism ; Mice ; Microbial Interactions/immunology ; Pathogen-Associated Molecular Pattern Molecules/immunology ; Pathogen-Associated Molecular Pattern Molecules/metabolism ; Receptors, Pattern Recognition/immunology ; Receptors, Pattern Recognition/metabolism ; Symbiosis ; T-Lymphocytes/immunology ; Toll-Like Receptor 4/metabolism ; Virus Diseases/immunology ; Virus Diseases/microbiology ; Viruses/pathogenicity
Chemical Substances	Cytokines ; Pathogen-Associated Molecular Pattern Molecules ; Receptors, Pattern Recognition ; Toll-Like Receptor 4 ; Interferons (9008-11-1)
Language	English
Publishing date	2019-06-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2019.05.009
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Article ; Online: On the road to ending the COVID-19 pandemic: Are we there yet?

Case, James Brett / Winkler, Emma S / Errico, John M / Diamond, Michael S

Virology

2021 Volume 557, Page(s) 70–85

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged into the human population in late 2019 and caused the global COVID-19 pandemic. SARS-CoV-2 has spread to more than 215 countries and infected many millions of people. Despite the ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged into the human population in late 2019 and caused the global COVID-19 pandemic. SARS-CoV-2 has spread to more than 215 countries and infected many millions of people. Despite the introduction of numerous governmental and public health measures to control disease spread, infections continue at an unabated pace, suggesting that effective vaccines and antiviral drugs will be required to curtail disease, end the pandemic, and restore societal norms. Here, we review the current developments in antibody and vaccine countermeasures to limit or prevent disease.
MeSH term(s)	Animals ; Antibodies, Viral/biosynthesis ; COVID-19/epidemiology ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19/therapy ; COVID-19/virology ; COVID-19 Vaccines/administration & dosage ; COVID-19 Vaccines/biosynthesis ; COVID-19 Vaccines/immunology ; Clinical Trials as Topic ; Disease Models, Animal ; Genetic Vectors/chemistry ; Genetic Vectors/immunology ; Humans ; Immunity, Innate/drug effects ; Immunization, Passive/methods ; Immunogenicity, Vaccine ; Pandemics ; Patient Safety ; SARS-CoV-2/drug effects ; SARS-CoV-2/immunology ; SARS-CoV-2/pathogenicity ; Vaccines, Attenuated ; Vaccines, DNA ; Vaccines, Subunit ; Vaccines, Virus-Like Particle/administration & dosage ; Vaccines, Virus-Like Particle/biosynthesis ; Vaccines, Virus-Like Particle/immunology ; COVID-19 Serotherapy
Chemical Substances	Antibodies, Viral ; COVID-19 Vaccines ; Vaccines, Attenuated ; Vaccines, DNA ; Vaccines, Subunit ; Vaccines, Virus-Like Particle
Language	English
Publishing date	2021-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2021.02.003
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Article: Nasally-delivered interferon-λ protects mice against upper and lower respiratory tract infection of SARS-CoV-2 variants including Omicron.

Chong, Zhenlu / Karl, Courtney E / Halfmann, Peter J / Kawaoka, Yoshihiro / Winkler, Emma S / Yu, Jinsheng / Diamond, Michael S

bioRxiv : the preprint server for biology

2022

Abstract: Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with SARS-CoV-2 infection, variants with constellations of mutations in the spike gene threaten their efficacy. Accordingly, antiviral ... ...

Abstract	Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with SARS-CoV-2 infection, variants with constellations of mutations in the spike gene threaten their efficacy. Accordingly, antiviral interventions that are resistant to further virus evolution are needed. The host-derived cytokine IFN-λ has been proposed as a possible treatment based on correlative studies in human COVID-19 patients. Here, we show IFN-λ protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1.529 (Omicron)variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally-delivered IFN-λ2 limited infection of historical or variant (B.1.351 and B.1.1.529) SARS-CoV-2 strains in the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-λ was produced preferentially in epithelial cells and acted on radio-resistant cells to protect against of SARS-CoV-2 infection. Thus, inhaled IFN-λ may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures.
Language	English
Publishing date	2022-01-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.01.21.477296
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Article ; Online: More efficient formation of longer-term representations for word forms at birth can be linked to better language skills at 2 years.

Suppanen, Emma / Winkler, István / Kujala, Teija / Ylinen, Sari

Developmental cognitive neuroscience

2022 Volume 55, Page(s) 101113

Abstract: Infants are able to extract words from speech early in life. Here we show that the quality of forming longer-term representations for word forms at birth predicts expressive language ability at the age of two years. Seventy-five neonates were ... ...

Abstract	Infants are able to extract words from speech early in life. Here we show that the quality of forming longer-term representations for word forms at birth predicts expressive language ability at the age of two years. Seventy-five neonates were familiarized with two spoken disyllabic pseudowords. We then tested whether the neonate brain predicts the second syllable from the first one by presenting a familiarized pseudoword frequently, and occasionally violating the learned syllable combination by different rare pseudowords. Distinct brain responses were elicited by predicted and unpredicted word endings, suggesting that the neonates had learned the familiarized pseudowords. The difference between responses to predicted and unpredicted pseudowords indexing the quality of word-form learning during familiarization significantly correlated with expressive language scores (the mean length of utterance) at 24 months in the same infant. These findings suggest that 1) neonates can memorize disyllabic words so that a learned first syllable generates predictions for the word ending, and 2) early individual differences in the quality of word-form learning correlate with language skills. This relationship helps early identification of infants at risk for language impairment.
MeSH term(s)	Child, Preschool ; Humans ; Infant ; Infant, Newborn ; Language ; Learning/physiology ; Speech ; Speech Perception/physiology ; Verbal Learning/physiology
Language	English
Publishing date	2022-05-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2572271-2
ISSN	1878-9307 ; 1878-9307
ISSN (online)	1878-9307
ISSN	1878-9307
DOI	10.1016/j.dcn.2022.101113
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Article ; Online: Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron.

Chong, Zhenlu / Karl, Courtney E / Halfmann, Peter J / Kawaoka, Yoshihiro / Winkler, Emma S / Keeler, Shamus P / Holtzman, Michael J / Yu, Jinsheng / Diamond, Michael S

Cell reports

2022 Volume 39, Issue 6, Page(s) 110799

Abstract: Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, variants with constellations of mutations in the spike gene ... ...

Abstract	Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, variants with constellations of mutations in the spike gene jeopardize their efficacy. Accordingly, antiviral interventions that are resistant to further virus evolution are needed. The host-derived cytokine interferon lambda (IFN-λ) has been proposed as a possible treatment based on studies in human coronavirus 2019 (COVID-19) patients. Here, we show that IFN-λ protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1.529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally delivered IFN-λ2 limits infection of historical or variant SARS-CoV-2 strains in the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-λ is produced preferentially in epithelial cells and acts on radio-resistant cells to protect against SARS-CoV-2 infection. Thus, inhaled IFN-λ may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/prevention & control ; Humans ; Interferons ; Mice ; Mice, Transgenic ; SARS-CoV-2 ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Interferons (9008-11-1)
Language	English
Publishing date	2022-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110799
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Article ; Online: Long-term eltrombopag for bone marrow failure depletes iron.

Young, David J / Fan, Xing / Groarke, Emma M / Patel, Bhavisha / Desmond, Ronan / Winkler, Thomas / Larochelle, Andre / Calvo, Katherine R / Young, Neal S / Dunbar, Cynthia E

American journal of hematology

2022 Volume 97, Issue 6, Page(s) 791–801

Abstract: Eltrombopag (EPAG) has been approved for the treatment of aplastic anemia and for immune thrombocytopenia, and a subset of patients require long-term therapy. Due to polyvalent cation chelation, prolonged therapy leads to previously underappreciated iron ...

Abstract	Eltrombopag (EPAG) has been approved for the treatment of aplastic anemia and for immune thrombocytopenia, and a subset of patients require long-term therapy. Due to polyvalent cation chelation, prolonged therapy leads to previously underappreciated iron depletion. We conducted a retrospective review of patients treated at the NIH for aplastic anemia, myelodysplastic syndrome, and unilineage cytopenias, comparing those treated with EPAG to a historical cohort treated with immunosuppression without EPAG. We examined iron parameters, duration of therapy, response assessment, relapse rates, and common demographic parameters. We included 521 subjects treated with (n = 315) or without EPAG (n = 206) across 11 studies with multiyear follow-up (3.6 vs. 8.5 years, respectively). Duration of EPAG exposure correlated with ferritin reduction (p = 4 × 10
MeSH term(s)	Anemia, Aplastic/drug therapy ; Benzoates/adverse effects ; Ferritins ; Humans ; Hydrazines ; Iron/therapeutic use ; Iron Overload/chemically induced ; Iron Overload/etiology ; Pancytopenia/chemically induced ; Pyrazoles ; Recurrence ; Thrombocytopenia/chemically induced
Chemical Substances	Benzoates ; Hydrazines ; Pyrazoles ; Ferritins (9007-73-2) ; Iron (E1UOL152H7) ; eltrombopag (S56D65XJ9G)
Language	English
Publishing date	2022-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	196767-8
ISSN	1096-8652 ; 0361-8609
ISSN (online)	1096-8652
ISSN	0361-8609
DOI	10.1002/ajh.26543
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Article ; Online: Nasally-delivered interferon-λ protects mice against upper and lower respiratory tract infection of SARS-CoV-2 variants including Omicron

Chong, Zhenlu / Karl, Courtney E / Halfmann, Peter J. / Kawaoka, Yoshihiro / Winkler, Emma S / Yu, Jinsheng / Diamond, Michael S.

bioRxiv

Abstract	Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with SARS-CoV-2 infection, variants with constellations of mutations in the spike gene threaten their efficacy. Accordingly, antiviral interventions that are resistant to further virus evolution are needed. The host-derived cytokine IFN-λ has been proposed as a possible treatment based on correlative studies in human COVID-19 patients. Here, we show IFN-λ protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1.529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally-delivered IFN-λ2 limited infection of historical or variant (B.1.351 and B.1.1.529) SARS-CoV-2 strains in the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-λ was produced preferentially in epithelial cells and acted on radio-resistant cells to protect against of SARS-CoV-2 infection. Thus, inhaled IFN-λ may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures.
Keywords	covid19
Language	English
Publishing date	2022-01-24
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.01.21.477296
Database	COVID19

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Article ; Online: MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2.

McCarthy, Mary K / Reynoso, Glennys V / Winkler, Emma S / Mack, Matthias / Diamond, Michael S / Hickman, Heather D / Morrison, Thomas E

PLoS pathogens

2020 Volume 16, Issue 1, Page(s) e1008292

Abstract: Humoral immune responses initiate in the lymph node draining the site of viral infection (dLN). Some viruses subvert LN B cell activation; however, our knowledge of viral hindrance of B cell responses of important human pathogens is lacking. Here, we ... ...

Abstract	Humoral immune responses initiate in the lymph node draining the site of viral infection (dLN). Some viruses subvert LN B cell activation; however, our knowledge of viral hindrance of B cell responses of important human pathogens is lacking. Here, we define mechanisms whereby chikungunya virus (CHIKV), a mosquito-transmitted RNA virus that causes outbreaks of acute and chronic arthritis in humans, hinders dLN antiviral B cell responses. Infection of WT mice with pathogenic, but not acutely cleared CHIKV, induced MyD88-dependent recruitment of monocytes and neutrophils to the dLN. Blocking this influx improved lymphocyte accumulation, dLN organization, and CHIKV-specific B cell responses. Both inducible nitric oxide synthase (iNOS) and the phagocyte NADPH oxidase (Nox2) contributed to impaired dLN organization and function. Infiltrating monocytes expressed iNOS through a local IRF5- and IFNAR1-dependent pathway that was partially TLR7-dependent. Together, our data suggest that pathogenic CHIKV triggers the influx and activation of monocytes and neutrophils in the dLN that impairs virus-specific B cell responses.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; Chikungunya Fever/immunology ; Chikungunya Fever/virology ; Chikungunya virus/physiology ; Humans ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/immunology ; Lymph Nodes/immunology ; Lymph Nodes/virology ; Mice, Inbred C57BL ; Mice, Knockout ; Monocytes/immunology ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/immunology ; NADPH Oxidase 2/genetics ; NADPH Oxidase 2/immunology ; Neutrophils/immunology ; Nitric Oxide Synthase Type II/genetics ; Nitric Oxide Synthase Type II/immunology
Chemical Substances	Interferon Regulatory Factors ; Irf5 protein, mouse ; Myd88 protein, mouse ; Myeloid Differentiation Factor 88 ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nos2 protein, mouse (EC 1.14.13.39) ; Cybb protein, mouse (EC 1.6.3.-) ; NADPH Oxidase 2 (EC 1.6.3.-)
Keywords	covid19
Language	English
Publishing date	2020-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1008292
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Article ; Online: Evaluation of Outcomes Following Focal Ablative Therapy for Treatment of Localized Clinically Significant Prostate Cancer in Patients >70 Years: A Multi-institute, Multi-energy 15-Year Experience.

The Journal of urology

2023 Volume 210, Issue 1, Page(s) 108–116

Abstract: Purpose: In older patients who do not wish to undergo watchful waiting, focal therapy could be an alternative to the more morbid radical treatment. We evaluated the role of focal therapy in patients 70 years and older as an alternative management ... ...

Abstract	Purpose: In older patients who do not wish to undergo watchful waiting, focal therapy could be an alternative to the more morbid radical treatment. We evaluated the role of focal therapy in patients 70 years and older as an alternative management modality. Materials and methods: A total of 649 patients across 11 UK sites receiving focal high-intensity focused ultrasound or cryotherapy between June 2006 and July 2020 reported within the UK-based HEAT (HIFU Evaluation and Assessment of Treatment) and ICE (International Cryotherapy Evaluation) registries were evaluated. Primary outcome was failure-free survival, defined by need for more than 1 focal reablation, progression to radical treatment, development of metastases, need for systemic treatment, or prostate cancer-specific death. This was compared to the failure-free survival in patients undergoing radical treatment via a propensity score weighted analysis. Results: Median age was 74 years (IQR: 72, 77) and median follow-up 24 months (IQR: 12, 41). Sixty percent had intermediate-risk disease and 35% high-risk disease. A total of 113 patients (17%) required further treatment. Sixteen had radical treatment and 44 required systemic treatment. Failure-free survival was 82% (95% CI: 76%-87%) at 5 years. Comparing patients who had radical therapy to those who had focal therapy, 5-year failure-free survival was 96% (95% CI: 93%-100%) and 82% (95% CI: 75%-91%) respectively ( Conclusions: We propose focal therapy to be an effective management option for the older or comorbid patient who is unsuitable for or not willing to undergo radical treatment.
MeSH term(s)	Aged ; Humans ; Male ; Androgen Antagonists ; Prostate/pathology ; Prostate-Specific Antigen ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/surgery ; Treatment Outcome ; Ablation Techniques
Chemical Substances	Androgen Antagonists ; Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2023-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	3176-8
ISSN	1527-3792 ; 0022-5347
ISSN (online)	1527-3792
ISSN	0022-5347
DOI	10.1097/JU.0000000000003443
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Article ; Online: Forms of Community Engagement in Neighborhood Food Retail: Healthy Community Stores Case Study Project.

Kaur, Ravneet / Winkler, Megan R / John, Sara / DeAngelo, Julia / Dombrowski, Rachael D / Hickson, Ashley / Sundermeir, Samantha M / Kasprzak, Christina M / Bode, Bree / Hill, Alex B / Lewis, Emma C / Colon-Ramos, Uriyoan / Munch, Jake / Witting, Lillian L / Odoms-Young, Angela / Gittelsohn, Joel / Leone, Lucia A

International journal of environmental research and public health

2022 Volume 19, Issue 12

Abstract: ... case study methodology was utilized among seven retailers in urban U.S. settings, which collected multiple ...

Abstract	Community engagement is well established as a key to improving public health. Prior food environment research has largely studied community engagement as an intervention component, leaving much unknown about how food retailers may already engage in this work. The purpose of this study was to explore the community engagement activities employed by neighborhood food retailers located in lower-income communities with explicit health missions to understand the ways stores involve and work with their communities. A multiple case study methodology was utilized among seven retailers in urban U.S. settings, which collected multiple sources of data at each retailer, including in-depth interviews, store manager sales reports, store observations using the Nutrition Environment Measures Survey for Stores, public documents, and websites. Across-case analysis was performed following Stake's multiple case study approach. Results indicated that retailers employed a wide variety of forms of community engagement within their communities, including Outreach, Building Relationships through Customer Relations, Giving Back, Partnering with Community Coalitions, and Promoting Community Representation and Inclusiveness. Strategies that built relationships through customer relations were most common across stores; whereas few stores demonstrated community inclusiveness where members participated in store decision making. Findings provide a more comprehensive view of the ways local food retailers aim to develop and sustain authentic community relationships. Additional research is needed to evaluate the impact of community engagement activities on improving community health.
MeSH term(s)	Commerce ; Food ; Food Supply ; Marketing ; Residence Characteristics
Language	English
Publishing date	2022-06-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph19126986
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