Abstract
Axion-like particles (ALPs) are well-motivated extensions of the Standard Model of Particle Physics and a generic prediction of some string theories. X-ray observations of bright active ...galactic nuclei (AGNs) hosted by rich clusters of galaxies are excellent probes of very-light ALPs, with masses
log
(
m
a
/
eV
)
<
−
12.0
. We evaluate the potential of future X-ray observatories, particularly Athena and the proposed AXIS, to constrain ALPs via observations of cluster-hosted AGNs, taking NGC 1275 in the Perseus cluster as our exemplar. Assuming perfect knowledge of the instrument calibration, we show that a modest exposure (200 ks) of NGC 1275 by Athena permits us to exclude all photon–ALP couplings
g
a
γ
> 6.3 × 10
−14
GeV
−1
at the 95% confidence level, as previously shown by Conlon et al., representing a factor of 10 improvement over current limits. We then proceed to assess the impact of realistic calibration uncertainties on the Athena projection by applying a standard Cash likelihood procedure, showing the projected constraints on
g
a
γ
weaken by a factor of 10 (back to the current most sensitive constraints). However, we show how the use of a deep neural network can disentangle the energy-dependent features induced by instrumental miscalibration and those induced by photon–ALP mixing, allowing us to recover most of the sensitivity to the ALP physics. In our explicit demonstration, the machine learning applied allows us to exclude
g
a
γ
> 2.0 × 10
−13
GeV
−1
, complementing the projected constraints of next-generation ALP dark matter birefringent cavity searches for very-light ALPs. Finally, we show that a 200 ks AXIS/on-axis observation of NGC 1275 will tighten the current best constraints on very-light ALPs by a factor of 3.
Abstract
Axion-like particles (ALPs) are a well-motivated extension to the standard model of particle physics, and X-ray observations of cluster-hosted AGN currently place the most stringent ...constraints on the ALP coupling to electromagnetism,
g
a
γ
, for very light ALPs (
m
a
≲ 10
−11
eV). We revisit limits obtained by Reynolds et al. using Chandra X-ray grating spectroscopy of NGC 1275, the central AGN in the Perseus cluster, examining the impact of the X-ray spectral model and magnetic field model. We also present a new publicly available code,
ALPro
, which we use to solve the ALP propagation problem. We discuss evidence for turbulent magnetic fields in Perseus and show that it can be important to resolve the magnetic field structure on scales below the coherence length. We reanalyze the NGC 1275 X-ray spectra using an improved data reduction and baseline spectral model. We find the limits are insensitive to whether a partially covering absorber is used in the fits. At low
m
a
(
m
a
≲ 10
−13
eV), we find marginally weaker limits on
g
a
γ
(by 0.1–0.3 dex) with different magnetic field models, compared to Model B from Reynolds et al. (2020). A Gaussian random field (GRF) model designed to mimic ∼50 kpc scale coherent structures also results in only slightly weaker limits. We conclude that the existing Model B limits are robust assuming that
β
pl
≈ 100, and are insensitive to whether cell-based or GRF methods are used. However, astrophysical uncertainties regarding the strength and structure of cluster magnetic fields persist, motivating high-sensitivity RM observations and tighter constraints on the radial profile of
β
pl
.
Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, but also suffer greater immunopathology and autoimmune disease. We ...here describe, in a cohort of > 170 in utero HIV-infected infants from KwaZulu-Natal, South Africa, fetal immune sex differences resulting in a 1.5-2-fold increased female susceptibility to intrauterine HIV infection. Viruses transmitted to females have lower replicative capacity (p = 0.0005) and are more type I interferon-resistant (p = 0.007) than those transmitted to males. Cord blood cells from females of HIV-uninfected sex-discordant twins are more activated (p = 0.01) and more susceptible to HIV infection in vitro (p = 0.03). Sex differences in outcome include superior maintenance of aviraemia among males (p = 0.007) that is not explained by differential antiretroviral therapy adherence. These data demonstrate sex-specific innate immune selection of HIV associated with increased female susceptibility to in utero infection and enhanced functional cure potential among infected males.
More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have ...not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T-cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-γ ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE-2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA*B*44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B*44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy.
In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in ...vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.
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•Antibody responses after SARS-CoV-2 mRNA vaccination target RBD, NTD, and S2•SARS-CoV-2 mRNA vaccination induces a high rate of non-neutralizing antibodies•Crossreactive antibodies to seasonal β-coronaviruses are induced by vaccination•Variant mutation N501Y enhances affinity to human ACE2 while E484K reduces it
An analysis of mRNA vaccine-induced polyclonal antibodies and plasmablast-derived monoclonal antibodies from individuals vaccinated against SARS-CoV-2 identifies a high proportion of non-neutralizing antibodies and the induction of cross-reactive antibodies to seasonal coronaviruses and also maps the regions in the spike protein that are targeted, even among viral variants.
Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation ...of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC50 ≈ 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.
Genomics and the origin of species Seehausen, Ole; Butlin, Roger K; Keller, Irene ...
Nature reviews. Genetics,
03/2014, Volume:
15, Issue:
3
Journal Article
Peer reviewed
Open access
Speciation is a fundamental evolutionary process, the knowledge of which is crucial for understanding the origins of biodiversity. Genomic approaches are an increasingly important aspect of this ...research field. We review current understanding of genome-wide effects of accumulating reproductive isolation and of genomic properties that influence the process of speciation. Building on this work, we identify emergent trends and gaps in our understanding, propose new approaches to more fully integrate genomics into speciation research, translate speciation theory into hypotheses that are testable using genomic tools and provide an integrative definition of the field of speciation genomics.
Lack of disease during chronic human cytomegalovirus (CMV) infection depends on the maintenance of a high-frequency CMV-specific T cell response. The composition of the T cell receptor (TCR) ...repertoire underlying this response remains poorly characterised, especially within African populations in which CMV is endemic from infancy. Here we focus on the immunodominant CD8+ T cell response to the immediate-early 2 (IE-2)-derived epitope NEGVKAAW (NW8) restricted by HLA-B*44:03, a highly prevalent response in African populations, which in some subjects represents >10% of the circulating CD8+ T cells. Using pMHC multimer staining and sorting of NW8-specific T cells, the TCR repertoire raised against NW8 was characterised here using high-throughput sequencing in 20 HLA-B*44:03 subjects. We found that the CD8+ T cell repertoire raised in response to NW8 was highly skewed and featured preferential use of a restricted set of V and J gene segments. Furthermore, as often seen in immunity against ancient viruses like CMV and Epstein-Barr virus (EBV), the response was strongly dominated by identical TCR sequences shared by multiple individuals, or "public" TCRs. Finally, we describe a pair "superdominant" TCR clonotypes, which were germline or nearly germline-encoded and produced at remarkably high frequencies in certain individuals, with a single CMV-specific clonotype representing up to 17% of all CD8+ T cells. Given the magnitude of the NW8 response, we propose that this major skewing of CMV-specific immunity leads to massive perturbations in the overall TCR repertoire in HLA-B*44:03 individuals.
Abstract
Background
Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on ...infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown.
Methods
Peripheral blood total HIV DNA from 164 early treated (day 0–21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants.
Results
Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7–4.8) did not correlate with age at cART initiation (0–21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound.
Conclusions
With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.
Peripheral blood HIV DNA levels from 164 South African in utero HIV-infected infants showed that with antiretroviral mother-to-child transmission prophylaxis, combination antiretroviral therapy initiation timing in the first 3 weeks of life does not significantly influence latent HIV reservoir size.
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