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Article ; Online: Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity.

Yang, Zemin / Johnson, Bryan A / Meliopoulos, Victoria A / Ju, Xiaohui / Zhang, Peipei / Hughes, Michael P / Wu, Jinjun / Koreski, Kaitlin P / Clary, Jemma E / Chang, Ti-Cheng / Wu, Gang / Hixon, Jeff / Duffner, Jay / Wong, Kathy / Lemieux, Rene / Lokugamage, Kumari G / Alvarado, R Elias / Crocquet-Valdes, Patricia A / Walker, David H /

Plante, Kenneth S / Plante, Jessica A / Weaver, Scott C / Kim, Hong Joo / Meyers, Rachel / Schultz-Cherry, Stacey / Ding, Qiang / Menachery, Vineet D / Taylor, J Paul

Cell reports

2024 Volume 43, Issue 3, Page(s) 113965

Abstract: G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits stress granule ... ...

Abstract	G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits stress granule assembly and interacts with G3BP1/2 via an ITFG motif, including residue F17, in the N protein. Prior studies examining the impact of the G3PB1-N interaction on SARS-CoV-2 replication have produced inconsistent findings, and the role of this interaction in pathogenesis is unknown. Here, we use structural and biochemical analyses to define the residues required for G3BP1-N interaction and structure-guided mutagenesis to selectively disrupt this interaction. We find that N-F17A mutation causes highly specific loss of interaction with G3BP1/2. SARS-CoV-2 N-F17A fails to inhibit stress granule assembly in cells, has decreased viral replication, and causes decreased pathology in vivo. Further mechanistic studies indicate that the N-F17-mediated G3BP1-N interaction promotes infection by limiting sequestration of viral genomic RNA (gRNA) into stress granules.
MeSH term(s)	Humans ; SARS-CoV-2/genetics ; DNA Helicases/metabolism ; RNA Helicases/metabolism ; RNA Recognition Motif Proteins/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism ; Virulence ; COVID-19 ; RNA, Guide, CRISPR-Cas Systems ; Nucleocapsid Proteins ; Virus Replication ; RNA, Viral/genetics
Chemical Substances	DNA Helicases (EC 3.6.4.-) ; RNA Helicases (EC 3.6.4.13) ; RNA Recognition Motif Proteins ; Poly-ADP-Ribose Binding Proteins ; RNA, Guide, CRISPR-Cas Systems ; Nucleocapsid Proteins ; RNA, Viral ; G3BP1 protein, human (EC 3.6.4.12)
Language	English
Publishing date	2024-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.113965
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Article ; Online: Diverse Durham collection phages demonstrate complex BREX defense responses.

Kelly, Abigail / Went, Sam C / Mariano, Giuseppina / Shaw, Liam P / Picton, David M / Duffner, Samuel J / Coates, Isabel / Herdman-Grant, Ryan / Gordeeva, Julia / Drobiazko, Alena / Isaev, Artem / Lee, Yan-Jiun / Luyten, Yvette / Morgan, Richard D / Weigele, Peter / Severinov, Konstantin / Wenner, Nicolas / Hinton, Jay C D / Blower, Tim R

Applied and environmental microbiology

2023 Volume 89, Issue 9, Page(s) e0062323

Abstract: Bacteriophages (phages) outnumber bacteria ten-to-one and cause infections at a rate of ... ...

Abstract	Bacteriophages (phages) outnumber bacteria ten-to-one and cause infections at a rate of 10
MeSH term(s)	Bacteriophages/physiology ; Phylogeny ; Biological Evolution ; Bacteria ; England
Language	English
Publishing date	2023-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	223011-2
ISSN	1098-5336 ; 0099-2240
ISSN (online)	1098-5336
ISSN	0099-2240
DOI	10.1128/aem.00623-23
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Article ; Online: The possible perils of targeted therapy.

Duffner, U / Abdel-Mageed, A / Younge, J / Tornga, C / Scott, K / Staddon, J / Elliott, K / Stumph, J / Kidd, P

Leukemia

2016 Volume 30, Issue 7, Page(s) 1619–1621

MeSH term(s)	Antibodies, Bispecific/adverse effects ; Antineoplastic Agents, Immunological/adverse effects ; Female ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Leukemia, Monocytic, Acute/etiology ; Leukemia, Monocytic, Acute/genetics ; Molecular Targeted Therapy/adverse effects ; Myeloid-Lymphoid Leukemia Protein/genetics ; Neoplasms, Second Primary/genetics ; Neoplasms, Second Primary/pathology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Young Adult
Chemical Substances	Antibodies, Bispecific ; Antineoplastic Agents, Immunological ; KMT2A protein, human ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; blinatumomab (4FR53SIF3A) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
Language	English
Publishing date	2016-02-09
Publishing country	England
Document type	Case Reports ; Letter
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/leu.2016.18
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Article: Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication.

Yang, Zemin / Johnson, Bryan A / Meliopoulos, Victoria A / Ju, Xiaohui / Zhang, Peipei / Hughes, Michael P / Wu, Jinjun / Koreski, Kaitlin P / Chang, Ti-Cheng / Wu, Gang / Hixon, Jeff / Duffner, Jay / Wong, Kathy / Lemieux, Rene / Lokugamage, Kumari G / Alvardo, Rojelio E / Crocquet-Valdes, Patricia A / Walker, David H / Plante, Kenneth S /

Plante, Jessica A / Weaver, Scott C / Kim, Hong Joo / Meyers, Rachel / Schultz-Cherry, Stacey / Ding, Qiang / Menachery, Vineet D / Taylor, J Paul

bioRxiv : the preprint server for biology

2023

Abstract: G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS- ... ...

Abstract	G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP1-N interaction in the context of viral infection remain unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively and reciprocally disrupt their interaction. We found that mutation of F17 within the N protein led to selective loss of interaction with G3BP1 and consequent failure of the N protein to disrupt stress granule assembly. Introduction of SARS-CoV-2 bearing an F17A mutation resulted in a significant decrease in viral replication and pathogenesis in vivo, indicating that the G3BP1-N interaction promotes infection by suppressing the ability of G3BP1 to form stress granules.
Language	English
Publishing date	2023-06-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.29.546885
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Article: Treatment of children with simple febrile seizures: the AAP practice parameter. American Academy of Pediatrics.

Baumann, R J / Duffner, P K

Pediatric neurology

2000 Volume 23, Issue 1, Page(s) 11–17

Abstract: Febrile seizures are the most common seizure disorder in childhood, occurring in 2-5% of children. Despite their frequency, there has been little unanimity of opinion regarding the need for long-term antiepileptic therapy. As such, the American Academy ... ...

Abstract	Febrile seizures are the most common seizure disorder in childhood, occurring in 2-5% of children. Despite their frequency, there has been little unanimity of opinion regarding the need for long-term antiepileptic therapy. As such, the American Academy of Pediatrics formulated a subcommittee to study the subject. A Practice Parameter was developed that addressed the issue of whether continuous or intermittent antiepileptic therapy is necessary for children with simple febrile seizures. The committee determined that with the exception of a high rate of recurrence, no long-term adverse effects of simple febrile seizures have been identified. The risk of developing epilepsy is extremely low and, even in those patients who do, there is no evidence that recurrent simple febrile seizures produce structural central nervous system damage. Also, there is no evidence that recurrent simple febrile seizures cause either learning problems or premature death. The committee concluded that although there is the evidence that continuous antiepileptic therapy with phenobarbital or valproic acid and intermittent therapy with diazepam are effective in reducing the risk of recurrence, the potential toxicities associated with antiepileptic therapy outweigh the relatively minor risks associated with simple febrile seizures. As such, long-term treatment is not recommended.
MeSH term(s)	Adolescent ; Anticonvulsants/administration & dosage ; Anticonvulsants/adverse effects ; Child ; Child, Preschool ; Clinical Trials as Topic ; Drug Therapy, Combination ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Pediatrics/standards ; Phenobarbital/administration & dosage ; Phenobarbital/adverse effects ; Risk Assessment ; Secondary Prevention ; Seizures, Febrile/drug therapy ; Seizures, Febrile/prevention & control ; United States ; Valproic Acid/administration & dosage ; Valproic Acid/adverse effects
Chemical Substances	Anticonvulsants ; Valproic Acid (614OI1Z5WI) ; Phenobarbital (YQE403BP4D)
Language	English
Publishing date	2000-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	639164-3
ISSN	1873-5150 ; 0887-8994
ISSN (online)	1873-5150
ISSN	0887-8994
DOI	10.1016/s0887-8994(00)00148-x
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Article ; Online: A synopsis of the American Academy of Pediatrics' practice parameters on the evaluation and treatment of children with febrile seizures.

Duffner, P K / Baumann, R J

Pediatrics in review

1999 Volume 20, Issue 8, Page(s) 285–287

MeSH term(s)	Child ; Child, Preschool ; Electroencephalography ; Humans ; Infant ; Infant, Newborn ; Pediatrics/methods ; Practice Guidelines as Topic ; Recurrence ; Seizures, Febrile/blood ; Seizures, Febrile/diagnosis ; Seizures, Febrile/etiology ; Seizures, Febrile/therapy ; Spinal Puncture
Language	English
Publishing date	1999-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	774515-1
ISSN	1526-3347 ; 0191-9601
ISSN (online)	1526-3347
ISSN	0191-9601
DOI	10.1542/pir.20-8-285
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Zs.B 2595: 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 53: Show issues

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Article ; Online: Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication

Yang, Zemin / Johnson, Bryan A. / Meliopoulos, Victoria A. / Ju, Xiaohui / Zhang, Peipei / Hughes, Michael P. / Wu, Jinjun / Koreski, Kaitlin P. / Chang, Ti-Cheng / Wu, Gang / Hixon, Jeff / Duffner, Jay / Wong, Kathy / Lemieux, Rene / Lokugamage, Kumari G. / Alvardo, Rojelio E. / Crocquet-Valdes, Patricia A. / Walker, David H. / Plante, Kenneth S. /

Plante, Jessica A. / Weaver, Scott C. / Kim, Hong Joo / Meyers, Rachel / Schultz-Cherry, Stacey / Ding, Qiang / Menachery, Vineet D / Taylor, J Paul

bioRxiv

Abstract	G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP1-N interaction in the context of viral infection remain unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively and reciprocally disrupt their interaction. We found that mutation of F17 within the N protein led to selective loss of interaction with G3BP1 and consequent failure of the N protein to disrupt stress granule assembly. Introduction of SARS-CoV-2 bearing an F17A mutation resulted in a significant decrease in viral replication and pathogenesis in vivo, indicating that the G3BP1-N interaction promotes infection by suppressing the ability of G3BP1 to form stress granules.
Keywords	covid19
Language	English
Publishing date	2023-06-30
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.06.29.546885
Database	COVID19

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Article ; Online: Does galactocerebrosidase activity predict Krabbe phenotype?

Jalal, Kabir / Carter, Randy / Yan, Li / Barczykowski, Amy / Duffner, Patricia K

Pediatric neurology

2012 Volume 47, Issue 5, Page(s) 324–329

Abstract: ... context. Higher galactocerebrosidase activity was predictive of later symptom onset times (P = 0.0011 ... but did not predict survival after symptom onset (P = 0.9064) when controlling for the logarithm of age ...

Abstract	This study sought to determine whether galactocerebrosidase activity is predictive of Krabbe onset age, or of survival from onset when controlling for age at onset of signs. We analyzed data on 55 symptomatic patients from the Hunter James Kelly Research Institute's World-Wide Registry. They were tested for galactocerebrosidase activity at Jefferson Medical College (Philadelphia, PA), using survival models in a path model context. Higher galactocerebrosidase activity was predictive of later symptom onset times (P = 0.0011), but did not predict survival after symptom onset (P = 0.9064) when controlling for the logarithm of age at onset. No child with early infantile (aged 0-6 months) phenotype demonstrated galactocerebrosidase activity >0.1 nmol/hour/mg protein. Survival times within a given phenotype did not vary with galactocerebrosidase activity. Although low galactocerebrosidase activity does not predict phenotype, higher activity in the abnormal range (>0.1 nmol/hour/mg protein in this sample) was not identified in the early infantile variant. Galactocerebrosidase activity may be important to consider when predicting phenotype in the newborn screening population. Our findings provide empiric evidence that the upper end (0.15 nmol/hour/mg protein) of the high-risk galactocerebrosidase group in the New York State newborn screening program is conservatively appropriate.
MeSH term(s)	Age of Onset ; Biomarkers/blood ; Child ; Child, Preschool ; Enzyme Activation/physiology ; Galactosylceramidase/blood ; Humans ; Infant ; Infant, Newborn ; Leukocytes/enzymology ; Leukodystrophy, Globoid Cell/diagnosis ; Leukodystrophy, Globoid Cell/enzymology ; Leukodystrophy, Globoid Cell/genetics ; Phenotype ; Predictive Value of Tests ; Registries ; Survival Rate/trends
Chemical Substances	Biomarkers ; Galactosylceramidase (EC 3.2.1.46)
Language	English
Publishing date	2012-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639164-3
ISSN	1873-5150 ; 0887-8994
ISSN (online)	1873-5150
ISSN	0887-8994
DOI	10.1016/j.pediatrneurol.2012.07.003
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Article ; Online: Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor.

Farutin, Victor / Prod'homme, Thomas / McConnell, Kevin / Washburn, Nathaniel / Halvey, Patrick / Etzel, Carol J / Guess, Jamey / Duffner, Jay / Getchell, Kristen / Meccariello, Robin / Gutierrez, Bryan / Honan, Christopher / Zhao, Ganlin / Cilfone, Nicholas A / Gunay, Nur Sibel / Hillson, Jan L / DeLuca, David S / Saunders, Katherine C / Pappas, Dimitrios A /

Greenberg, Jeffrey D / Kremer, Joel M / Manning, Anthony M / Ling, Leona E / Capila, Ishan

Arthritis research & therapy

2019 Volume 21, Issue 1, Page(s) 216

Abstract: ... in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p ... 1.20 [95% CI = 1.03-1.41, p = 0.02]).: Conclusion: Differences in innate/adaptive immune cell ...

Abstract	Background: The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA). Methods: Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database. Results: A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p < 0.01) between the two cohorts. A baseline, response signature of increased innate cell types in responders compared to increased adaptive cell types in non-responders was identified in both cohorts. This result was further assessed by applying the cell type-specific analysis to five other publicly available RA datasets. Evaluation of the neutrophil-to-lymphocyte ratio at baseline in the remaining patients (n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03-1.41, p = 0.02]). Conclusion: Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.
MeSH term(s)	Adaptive Immunity/drug effects ; Adaptive Immunity/physiology ; Adult ; Aged ; Antirheumatic Agents/pharmacology ; Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/immunology ; Cohort Studies ; Female ; Gene Expression Profiling/methods ; Humans ; Immunity, Innate/drug effects ; Immunity, Innate/physiology ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Tumor Necrosis Factor-alpha/immunology
Chemical Substances	Antirheumatic Agents ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2019-10-23
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-019-1999-3
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Article: Changes in the approach to central nervous system tumors in childhood.

Duffner, P K / Cohen, M E

Pediatric clinics of North America

1992 Volume 39, Issue 4, Page(s) 859–877

Abstract: Current approaches to children with brain tumors are in a state of evolution. Currently, 50% of children with all types of brain tumors may be expected to survive 5 years. Therefore, the goals of neuro-oncology have broadened to include improved survival ...

Abstract	Current approaches to children with brain tumors are in a state of evolution. Currently, 50% of children with all types of brain tumors may be expected to survive 5 years. Therefore, the goals of neuro-oncology have broadened to include improved survival and improved quality of life. This article reviews changes in therapy that have altered survival as well as changes in therapy as a consequence of increasing recognition of complications and toxicity of treatment.
MeSH term(s)	Brain/radiation effects ; Brain Diseases/etiology ; Brain Neoplasms/therapy ; Child ; Glioma/therapy ; Humans ; Medulloblastoma/therapy ; Methotrexate/adverse effects ; Radiation Injuries
Chemical Substances	Methotrexate (YL5FZ2Y5U1)
Language	English
Publishing date	1992-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	215711-1
ISSN	1557-8240 ; 0031-3955
ISSN (online)	1557-8240
ISSN	0031-3955
DOI	10.1016/s0031-3955(16)38378-x
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