37 research outputs found
The Orbit of the Companion to HD 100453A: Binary-Driven Spiral Arms in a Protoplanetary Disk
HD 100453AB is a 10+/-2 Myr old binary whose protoplanetary disk was recently
revealed to host a global two-armed spiral structure. Given the relatively
small projected separation of the binary (1.05", or ~108 au), gravitational
perturbations by the binary seemed to be a likely driving force behind the
formation of the spiral arms. However, the orbit of these stars remained poorly
understood, which prevented a proper treatment of the dynamical influence of
the companion on the disk. We observed HD 100453AB between 2015-2017 utilizing
extreme adaptive optics systems on the Very Large Telescope and Magellan Clay
Telescope. We combined the astrometry from these observations with published
data to constrain the parameters of the binary's orbit to a=1.06"+/-0.09",
e=0.17+/-0.07, and i=32.5+/- 6.5 degrees. We utilized publicly available ALMA
CO data to constrain the inclination of the disk to i~28 degrees, which is
relatively co-planar with the orbit of the companion and consistent with
previous estimates from scattered light images. Finally, we input these
constraints into hydrodynamical and radiative transfer simulations to model the
structural evolution of the disk. We find that the spiral structure and
truncation of the circumprimary disk in HD 100453 are consistent with a
companion-dirven origin. Furthermore, we find that the primary star's rotation,
its outer disk, and the companion exhibit roughly the same direction of angular
momentum, and thus the system likely formed from the same parent body of
material.Comment: 28 pages, 11 figures, Accepted to Ap
Longitudinal Variations in Antibody Responses against SARS-CoV-2 Spike Epitopes upon Serial Vaccinations
The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted healthcare, the workforce, and worldwide socioeconomics. Multi-dose mono- or bivalent mRNA vaccine regimens have shown high efficacy in protection against SARSCoV- 2 and its emerging variants with varying degrees of efficacy. Amino acid changes, primarily in the receptor-binding domain (RBD), result in selection for viral infectivity, disease severity, and immune evasion. Therefore, many studies have centered around neutralizing antibodies that target the RBD and their generation achieved through infection or vaccination. Here, we conducted a unique longitudinal study, analyzing the effects of a three-dose mRNA vaccine regimen exclusively using the monovalent BNT162b2 (Pfizer/BioNTech) vaccine, systematically administered to nine previously uninfected (naïve) individuals. We compare changes in humoral antibody responses across the entire SARS-CoV-2 spike glycoprotein (S) using a high-throughput phage display technique (VirScan). Our data demonstrate that two doses of vaccination alone can achieve the broadest and highest magnitudes of anti-S response. Moreover, we present evidence of novel highly boosted non-RBD epitopes that strongly correlate with neutralization and recapitulate independent findings. These vaccine-boosted epitopes could facilitate multi-valent vaccine development and drug discovery
Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution
The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a Severe Acute Respiratory Syndrome-like disease with ∼43% mortality. Given the recent detection of virus in dromedary camels, zoonotic transfer of MERS-CoV to humans is suspected. In addition, little is known about the role of human neutralizing Ab (nAb) pressure as a driving force in MERS-CoV adaptive evolution. Here, we used a well-characterized nonimmune human Ab-phage library and a panning strategy with proteoliposomes and cells to identify seven human nAbs against the receptor-binding domain (RBD) of the MERS-CoV Spike protein. These nAbs bind to three different epitopes in the RBD and human dipeptidyl peptidase 4 (hDPP4) interface with subnanomolar/nanomolar binding affinities and block the binding of MERS-CoV Spike protein with its hDPP4 receptor. Escape mutant assays identified five amino acid residues that are critical for neutralization escape. Despite the close proximity of the three epitopes on the RBD interface, escape from one epitope did not have a major impact on neutralization with Abs directed to a different epitope. Importantly, the majority of escape mutations had negative impacts on hDPP4 receptor binding and viral fitness. To our knowledge, these results provide the first report on human nAbs against MERS-CoV that may contribute to MERS-CoV clearance and evolution. Moreover, in the absence of a licensed vaccine or antiviral for MERS, this panel of nAbs offers the possibility of developing human mAb-based immunotherapy, especially for health-care workers
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Molecular Signatures of Hemagglutinin Stem-Directed Heterosubtypic Human Neutralizing Antibodies against Influenza A Viruses
Recent studies have shown high usage of the IGHV1-69 germline immunoglobulin gene for influenza hemagglutinin stem-directed broadly-neutralizing antibodies (HV1-69-sBnAbs). Here we show that a major structural solution for these HV1-69-sBnAbs is achieved through a critical triad comprising two CDR-H2 loop anchor residues (a hydrophobic residue at position 53 (Ile or Met) and Phe54), and CDR-H3-Tyr at positions 98±1; together with distinctive V-segment CDR amino acid substitutions that occur in positions sparse in AID/polymerase-η recognition motifs. A semi-synthetic IGHV1-69 phage-display library screen designed to investigate AID/polη restrictions resulted in the isolation of HV1-69-sBnAbs that featured a distinctive Ile52Ser mutation in the CDR-H2 loop, a universal CDR-H3 Tyr at position 98 or 99, and required as little as two additional substitutions for heterosubtypic neutralizing activity. The functional importance of the Ile52Ser mutation was confirmed by mutagenesis and by BCR studies. Structural modeling suggests that substitution of a small amino acid at position 52 (or 52a) facilitates the insertion of CDR-H2 Phe54 and CDR-H3-Tyr into adjacent pockets on the stem. These results support the concept that activation and expansion of a defined subset of IGHV1-69-encoded B cells to produce potent HV1-69-sBnAbs does not necessarily require a heavily diversified V-segment acquired through recycling/reentry into the germinal center; rather, the incorporation of distinctive amino acid substitutions by Phase 2 long-patch error-prone repair of AID-induced mutations or by random non-AID SHM events may be sufficient. We propose that these routes of B cell maturation should be further investigated and exploited as a pathway for HV1-69-sBnAb elicitation by vaccination
Nuclear-localized human respiratory syncytial virus NS1 protein modulates host gene transcription
Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in the pediatric, elderly, and immunocompromised individuals. RSV non-structural protein NS1 is a known cytosolic immune antagonist, but how NS1 modulates host responses remains poorly defined. Here, we observe NS1 partitioning into the nucleus of RSV-infected cells, including the human airway epithelium. Nuclear NS1 coimmunoprecipitates with Mediator complex and is chromatin associated. Chromatin-immunoprecipitation demonstrates enrichment of NS1 that overlaps Mediator and transcription factor binding within the promoters and enhancers of differentially expressed genes during RSV infection. Mutation of the NS1 C-terminal helix reduces NS1 impact on host gene expression. These data suggest that nuclear NS1 alters host responses to RSV infection by binding at regulatory elements of immune response genes and modulating host gene transcription. Our study identifies another layer of regulation by virally encoded proteins that shapes host response and impacts immunity to RSV
Proteomic identification, cDNA cloning and enzymatic activity of glutathione S-transferases from the generalist marine gastropod, Cyphoma gibbosum
Author Posting. © Elsevier B.V., 2008. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Archives of Biochemistry and Biophysics 478 (2008): 7-17, doi:10.1016/j.abb.2008.07.007.Glutathione S-transferases (GST) were characterized from the digestive gland of
Cyphoma gibbosum (Mollusca; Gastropoda), to investigate the possible role of these
detoxification enzymes in conferring resistance to allelochemicals present in its gorgonian coral
diet. We identified the collection of expressed cytosolic Cyphoma GST classes using a
proteomic approach involving affinity chromatography, HPLC and nanospray liquid
chromatography-tandem mass spectrometry (LC-MS/MS). Two major GST subunits were
identified as putative mu-class GSTs; while one minor GST subunit was identified as a putative
theta-class GST, apparently the first theta-class GST identified from a mollusc. Two Cyphoma
GST cDNAs (CgGSTM1 and CgGSTM2) were isolated by RT-PCR using primers derived from
peptide sequences. Phylogenetic analyses established both cDNAs as mu-class GSTs and
revealed a mollusc-specific subclass of the GST-mu clade. These results provide new insights
into metazoan GST diversity and the biochemical mechanisms used by marine organisms to cope
with their chemically defended prey.Support was provided by the WHOI-Cole Ocean Ventures Fund (KEW), the WHOI Ocean Life
Institute (KEW and MEH), a grant from Walter A. and Hope Noyes Smith (MEH), the National
Science Foundation Graduate Research Fellowship (KEW), and by the National Institutes of
Health (P42-ES007381 and R01-ES015912 to JVG)
The Science Performance of JWST as Characterized in Commissioning
This paper characterizes the actual science performance of the James Webb
Space Telescope (JWST), as determined from the six month commissioning period.
We summarize the performance of the spacecraft, telescope, science instruments,
and ground system, with an emphasis on differences from pre-launch
expectations. Commissioning has made clear that JWST is fully capable of
achieving the discoveries for which it was built. Moreover, almost across the
board, the science performance of JWST is better than expected; in most cases,
JWST will go deeper faster than expected. The telescope and instrument suite
have demonstrated the sensitivity, stability, image quality, and spectral range
that are necessary to transform our understanding of the cosmos through
observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures;
https://iopscience.iop.org/article/10.1088/1538-3873/acb29
Dynamics of Serum-Neutralizing Antibody Responses in Vaccinees through Multiple Doses of the BNT162b2 Vaccine
SARS-CoV-2 mRNA vaccines are administered as effective prophylactic measures for reducing virus transmission rates and disease severity. To enhance the durability of post-vaccination immunity and combat SARS-CoV-2 variants, boosters have been administered to two-dose vaccinees. However, long-term humoral responses following booster vaccination are not well characterized. A 16-member cohort of healthy SARS-CoV-2 naïve participants were enrolled in this study during a three-dose BNT162b2 vaccine series. Serum samples were collected from vaccinees over 420 days and screened for antigen (Ag)-specific antibody titers, IgG subclass distribution, and neutralizing antibody (nAb) responses. Vaccine boosting restored peak Ag-specific titers with sustained α-RBD IgG and IgA antibody responses when measured at six months post-boost. RBD- and spike-specific IgG4 antibody levels were markedly elevated in three-dose but not two-dose immune sera. Although strong neutralization responses were detected in two- and three-dose vaccine sera, these rapidly decayed to pre-immune levels by four and six months, respectively. While boosters enhanced serum IgG Ab reactivity and nAb responses against variant strains, all variants tested showed resistance to two- and three-dose immune sera. Our data reflect the poor durability of vaccine-induced nAb responses which are a strong predictor of protection from symptomatic SARS-CoV-2 infection. The induction of IgG4-switched humoral responses may permit extended viral persistence via the downregulation of Fc-mediated effector functions