(ProQuest: ... denotes formulae and/or non-USASCII text omitted) We present results from spectroscopic observations with the Michigan/Magellan Fiber System (M2FS) of 147 stellar targets along the ...line of sight to the newly discovered "ultrafaint" stellar systems Tucana 2 (Tuc 2) and Grus 1 (Gru 1). Based on simultaneous estimates of line of sight velocity and stellar-atmospheric parameters, we identify 8 and 7 stars as probable members of Tuc 2 and and Gru 1, respectively. Our sample for Tuc 2 is sufficient to resolve an internal velocity dispersion of ... km s super(-1) about a mean of ... km s super(-1)(solar rest frame), and to estimate a mean metallicity of Fe/H = ... These results place Tuc 2 on chemodynamical scaling relations followed by dwarf galaxies, suggesting a dominant dark matter component with dynamical mass ... M sub(middot in circle) enclosed within the central ~160 pc, and dynamical mass-to-light ratio ... M sub(middot in circle)/Lv .middot in circle. For Gru 1 we estimate a mean velocity of ... km s super(-1) and a mean metallicity of Fe/H = ... but our sample does not resolve Gru 1's velocity dispersion. The radial coordinates of Tuc 2 and Gru 1 in Galactic phase space suggest that their orbits are among the most energetic within a distance of <, ~ 300 kpc. Moreover, their proximity to each other in this space arises naturally if both objects are trailing the Large Magellanic Cloud.
The effectiveness of the BNT162b2 and ChAdOx1 vaccines against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections requires continuous re-evaluation, given the increasingly ...dominant B.1.617.2 (Delta) variant. In this study, we investigated the effectiveness of these vaccines in a large, community-based survey of randomly selected households across the United Kingdom. We found that the effectiveness of BNT162b2 and ChAdOx1 against infections (new polymerase chain reaction (PCR)-positive cases) with symptoms or high viral burden is reduced with the B.1.617.2 variant (absolute difference of 10-13% for BNT162b2 and 16% for ChAdOx1) compared to the B.1.1.7 (Alpha) variant. The effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity after second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positive cases but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher in vaccinated individuals after a prior infection and in younger adults. With B.1.617.2, infections occurring after two vaccinations had similar peak viral burden as those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with B.1.617.2.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Information on SARS-CoV-2 in representative community surveillance is limited, particularly cycle threshold (Ct) values (a proxy for viral load).
We included all positive nose and throat swabs 26 ...April 2020 to 13 March 2021 from the UK's national COVID-19 Infection Survey, tested by RT-PCR for the N, S, and ORF1ab genes. We investigated predictors of median Ct value using quantile regression.
Of 3,312,159 nose and throat swabs, 27,902 (0.83%) were RT-PCR-positive, 10,317 (37%), 11,012 (40%), and 6550 (23%) for 3, 2, or 1 of the N, S, and ORF1ab genes, respectively, with median Ct = 29.2 (~215 copies/ml; IQR Ct = 21.9-32.8, 14-56,400 copies/ml). Independent predictors of lower Cts (i.e. higher viral load) included self-reported symptoms and more genes detected, with at most small effects of sex, ethnicity, and age. Single-gene positives almost invariably had Ct > 30, but Cts varied widely in triple-gene positives, including without symptoms. Population-level Cts changed over time, with declining Ct preceding increasing SARS-CoV-2 positivity. Of 6189 participants with IgG S-antibody tests post-first RT-PCR-positive, 4808 (78%) were ever antibody-positive; Cts were significantly higher in those remaining antibody negative.
Marked variation in community SARS-CoV-2 Ct values suggests that they could be a useful epidemiological early-warning indicator.
Department of Health and Social Care, National Institutes of Health Research, Huo Family Foundation, Medical Research Council UK; Wellcome Trust.
Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second ...vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2-3 months after two ChAdOx1 doses, for 5-8 months after two BNT162b2 doses in those without prior infection and for 1-2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Most enveloped viruses need to use a sugar-mediated pathway in the infected human host cell to form their correct three-dimensional structures, which involves adding and processing glycans on viral ...envelope glycoproteins.2,3 The glycosylation process involves enzymes in the cell trimming the sugars of the viral glycoproteins for entry into this protein folding quality control pathway. Drugs that partially inhibit these enzymes prevent the virus from making proper use of this folding pathway and lead to inhibition of secretion of infectious virus.4–8 Over the past 25 years, we have developed a class of drugs called iminosugars—orally available sugar mimetics that are recognised by and inhibit these sugar processing enzymes that most enveloped viruses rely on.1 The family of iminosugars derive from the parent compound initially isolated from the leaves of the mulberry tree. Safety and efficacy data in animals accumulated over the past 20 years show that iminosugar derivatives reduce viral levels and increase survival in animal models of chronic hepatitis B infection,6 hepatitis C, Japanese encephalitis, influenza,9 and dengue.7,8 When tested in vitro against over 31 clinical HIV isolates, including HIV-1, HIV-2, and multidrug resistant strains, iminosugars are active against a diverse panel of HIV-1 from different genetic subtypes and geographical regions, and against HIV-2 isolates and mutants resistant to antiretrovirals.10 All HIV isolates tested were rendered non-infectious by iminosugar treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer cells accumulate genetic mutations in coding proteins that may be presented by HLA as neoantigenic peptides (peptide HLA, pHLA). T cells scan for neoantigenic pHLA by the T-cell receptor ...(TCR):CD3 complex. This complex has the dual function of binding pHLA, by the TCR, and triggering T-cell activation by CD3. Checkpoint therapy activates exhausted T cells to kill cancer cells and generally work best against tumors with high neoantigen burden and in patients with neoantigenic-reactive T cells. TCR T-cell engagers (TCE) are a novel class of immunotherapy that bypasses these two requirements by redirecting polyclonal T cells, regardless of their native specificity, to kill a cancer cell independent of neoantigen burden. This is accomplished through deconstructing the membrane-bound TCR:CD3 complex into a soluble bispecific protein comprised of a targeting domain (TCR) and activating domain (usually anti-CD3 single-chain variable fragment). The pool of targets for TCR TCE is larger than for antibody therapeutics and includes >90% of human intra- or extracellular proteins. Most tumor-associated antigens for solid tumors are intracellular and accessible only by a TCR therapeutic. Tebentafusp, a TCR TCE directed to a peptide derived from the gp100 melanoma protein presented by HLA*A02:01, demonstrated a survival benefit in metastatic uveal melanoma (mUM). This survival benefit highlights the promise of TCR TCEs because mUM is a solid tumor with a very low neoantigen burden and has poor response to checkpoints and chemotherapy. Other TCR TCE programs are now in clinical studies for a broader range of tumors.
ABSTRACT
The ultra-faint dwarf (UFD) galaxy Reticulum 2 (Ret 2) was recently discovered in images obtained by the Dark Energy Survey. We have observed the four brightest red giants in Ret 2 at high ...spectral resolution using the Michigan/
Magellan
Fiber System. We present detailed abundances for as many as 20 elements per star, including 12 elements heavier than the Fe group. We confirm previous detection of high levels of
r
-process material in Ret 2 (mean Eu/Fe = +1.69 ± 0.05) found in three of these stars (mean Fe/H = −2.88 ± 0.10). The abundances closely match the
r
-process pattern found in the well-studied metal-poor halo star CS 22892–052. Such
r
-process-enhanced stars have not been found in any other UFD galaxy, though their existence has been predicted by at least one model. The fourth star in Ret 2 (Fe/H = −3.42 ± 0.20) contains only trace amounts of Sr (Sr/Fe = −1.73 ± 0.43) and no detectable heavier elements. One
r
-process enhanced star is also enhanced in C (natal C/Fe ≈ +1.1). This is only the third such star known, which suggests that the nucleosynthesis sites leading to C and
r
-process enhancements are decoupled. The
r
-process-deficient star is enhanced in Mg (Mg/Fe = +0.81 ± 0.14), and the other three stars show normal levels of
α
-enhancement (mean Mg/Fe = +0.34 ± 0.03). The abundances of other
α
and Fe-group elements closely resemble those in UFD galaxies and metal-poor halo stars, suggesting that the nucleosynthesis that led to the large
r
-process enhancements either produced no light elements or produced light-element abundance signatures indistinguishable from normal supernovae.
In this report, investigators in the United Kingdom looked for clues regarding the rapid emergence and dissemination of the SARS-CoV-2 variant B.1.1.7 (alpha) at the end of 2020 and in early 2021.
Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants ...are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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