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1.
J Allergy Clin Immunol ; 153(6): 1634-1646, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38460680

RESUMO

BACKGROUND: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines. OBJECTIVE: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. METHODS: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements. RESULTS: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. CONCLUSIONS: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.


Assuntos
Vacina BNT162 , Vacinas contra COVID-19 , COVID-19 , Imunização Secundária , SARS-CoV-2 , Humanos , Pessoa de Meia-Idade , Masculino , Adulto , Feminino , Método Duplo-Cego , COVID-19/prevenção & controle , COVID-19/imunologia , SARS-CoV-2/imunologia , Idoso , Adolescente , Adulto Jovem , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Recidiva , Vacinação , Vacina de mRNA-1273 contra 2019-nCoV , Estudos Cross-Over
2.
Biochemistry ; 58(36): 3767-3776, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31403288

RESUMO

Pyk2 is a non-receptor tyrosine kinase that evolved from gene duplication of focal adhesion kinase (FAK) and subsequent functional specialization in the brain and hemopoietic cells. Pyk2 shares a domain organization with FAK, with an N-terminal regulatory FERM domain adjoining the kinase domain. FAK regulation involves integrin-mediated membrane clustering to relieve autoinhibitory interactions between FERM and kinase domains. Pyk2 regulation remains cryptic, involving Ca2+ influx and protein scaffolding. While the mechanism of the FAK FERM domain in autoinhibition is well-established, the regulatory role of the Pyk2 FERM is ambiguous. We probed the mechanisms of FERM-mediated autoinhibition of Pyk2 using hydrogen/deuterium exchange mass spectrometry and kinase activity profiling. The results reveal FERM-kinase interfaces that are responsible for autoinhibition. Pyk2 autoinhibition impacts the activation loop conformation. In addition, the autoinhibitory FERM-kinase interface exhibits allosteric linkage with the FERM basic patch conserved in both FAK and Pyk2.


Assuntos
Quinase 2 de Adesão Focal/antagonistas & inibidores , Quinase 2 de Adesão Focal/química , Domínios Proteicos , Sequência de Aminoácidos , Substituição de Aminoácidos , Ensaios Enzimáticos , Quinase 2 de Adesão Focal/genética , Humanos , Mutação , Conformação Proteica
3.
Clin Chem ; 70(8): 1087, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39087425
4.
Nat Commun ; 12(1): 4950, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400635

RESUMO

Upon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.


Assuntos
Receptores de Ativinas Tipo I/química , Receptores de Ativinas Tipo I/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/química , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Transdução de Sinais/fisiologia , Receptores de Ativinas Tipo I/genética , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Hipertensão Pulmonar Primária Familiar/metabolismo , Humanos , Ligantes , Modelos Moleculares , Mutação , Fosforilação , Ligação Proteica , Domínios Proteicos , Hipertensão Arterial Pulmonar , Espalhamento a Baixo Ângulo , Transdução de Sinais/genética , Proteínas Smad/metabolismo , Difração de Raios X
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