The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount ...of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A2A and inactive conformations of the A1 ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www.gpcrdb.org). This analysis provides novel insights into ligand binding, allosteric modulation, and signaling of the AR family.
Recent technological advances in membrane protein crystallization have resulted in a nearly exponential increase of available receptor structures. The AR family is an important example in this respect. Crystal structures of antagonist- and agonist-bound adenosine A2A receptor have recently been supplemented by a fully activated conformation in complex with a G-protein mimic, and by antagonist bound structures of the A1 receptor.
SDM experiments have been essential to identify residues involved in molecular interactions between ARs and their ligands. Leveraging on recent crystal structures, this vast amount of data can now be systematically classified and interconnected with chemical and structural information of ligands and receptors.
The mapping of mutational data onto crystal structures provides new understanding of molecular interactions involved in ligand recognition. Together with computational modeling, this can be used as a roadmap to create novel hypotheses and assist in the design of more systematic mutagenesis studies to answer remaining structural and functional questions.
IntroductionInvasive non-typhoidal Salmonella (iNTS) serovars are a major cause of community-acquired bloodstream infections in sub-Saharan Africa (SSA). In this setting, Salmonella enterica serovar ...Typhimurium accounts for two-thirds of infections and is associated with an estimated case fatality rate of 15%–20%. Several iNTS vaccine candidates are in early-stage assessment which—if found effective—would provide a valuable public health tool to reduce iNTS disease burden. The CHANTS study aims to develop a first-in-human Salmonella Typhimurium controlled human infection model, which can act as a platform for future vaccine evaluation, in addition to providing novel insights into iNTS disease pathogenesis.Methods and analysisThis double-blind, safety and dose-escalation study will randomise 40–80 healthy UK participants aged 18–50 to receive oral challenge with one of two strains of S. Typhimurium belonging to the ST19 (strain 4/74) or ST313 (strain D23580) lineages. 4/74 is a global strain often associated with diarrhoeal illness predominantly in high-income settings, while D23580 is an archetypal strain representing invasive disease-causing isolates found in SSA. The primary objective is to determine the minimum infectious dose (colony-forming unit) required for 60%–75% of participants to develop clinical or microbiological features of systemic salmonellosis. Secondary endpoints are to describe and compare the clinical, microbiological and immunological responses following challenge. Dose escalation or de-escalation will be undertaken by continual-reassessment methodology and limited within prespecified safety thresholds. Exploratory objectives are to describe mechanisms of iNTS virulence, identify putative immune correlates of protection and describe host–pathogen interactions in response to infection.Ethics and disseminationEthical approval has been obtained from the NHS Health Research Authority (London—Fulham Research Ethics Committee 21/PR/0051; IRAS Project ID 301659). The study findings will be disseminated in international peer-reviewed journals and presented at national/international stakeholder meetings. Study outcome summaries will be provided to both funders and participants.Trial registration numberNCT05870150
We present Keck spectroscopic observations of three probable high-redshift superluminous supernovae (SLSNe) from the Subaru HIgh-Z sUpernova CAmpaign (SHIZUCA), confirming redshifts of 1.851, 1.965, ...and 2.399. The host galaxies were selected for transient monitoring from multiband photometric redshifts. The supernovae are detected during their rise, and the classically scheduled spectra are collected near maximum light. The rest-frame far-ultraviolet (∼1000-2500 ) spectra include a significant host galaxy flux contribution, and we compare our host-galaxy-subtracted spectra to UV-luminous SNe from the literature. While the signal-to-noise ratios of the spectra presented here are sufficient for redshift confirmation, supernova spectroscopic type confirmation remains inconclusive. The success of the first SHIZUCA Keck spectroscopic follow-up program demonstrates that campaigns such as SHIZUCA are capable of identifying high-redshift SLSNe with sufficient accuracy, speed, and depth for rapid, well-cadenced, and informative follow-up.
We use the first compilation of 72 core-collapse supernovae (SNe) from the Palomar Transient Factory (PTF) to study their observed subtype distribution in dwarf galaxies compared to giant galaxies. ...Our sample is the largest single-survey, untargeted, spectroscopically classified, homogeneous collection of core-collapse events ever assembled, spanning a wide host-galaxy luminosity range (down to M{sub r} {approx} -14 mag) and including a substantial fraction (>20%) of dwarf (M{sub r} {>=} -18 mag) hosts. We find more core-collapse SNe in dwarf galaxies than expected and several interesting trends emerge. We use detailed subclassifications of stripped-envelope core-collapse SNe and find that all Type I core-collapse events occurring in dwarf galaxies are either SNe Ib or broad-lined SNe Ic (SNe Ic-BL), while 'normal' SNe Ic dominate in giant galaxies. We also see a significant excess of SNe IIb in dwarf hosts. We hypothesize that in lower metallicity hosts, metallicity-driven mass loss is reduced, allowing massive stars that would have appeared as 'normal' SNe Ic in metal-rich galaxies to retain some He and H, exploding as Ib/IIb events. At the same time, another mechanism allows some stars to undergo extensive stripping and explode as SNe Ic-BL (and presumably also as long-duration gamma-ray bursts). Our results are still limited by small-number statistics, and our measurements of the observed N(Ib/c)/N(II) number ratio in dwarf and giant hosts (0.25{sup +0.3}{sub -0.15} and 0.23{sup +0.11}{sub -0.08}, respectively; 1{sigma} uncertainties) are consistent with previous studies and theoretical predictions. As additional PTF data accumulate, more robust statistical analyses will be possible, allowing the evolution of massive stars to be probed via the dwarf-galaxy SN population.
As genetic information is transmitted through successive generations, it passes between pluripotent cells in the early embryo and germ cells in the developing foetus and adult animal. Tex19.1 encodes ...a protein of unknown function, whose expression is restricted to germ cells and pluripotent cells. During male spermatogenesis, Tex19.1 expression is highest in mitotic spermatogonia and diminishes as these cells differentiate and progress through meiosis. In pluripotent stem cells, Tex19.1 expression is also downregulated upon differentiation. However, it is not clear whether Tex19.1 has an essential function in germ cells or pluripotent stem cells, or what that function might be. To analyse the potential role of Tex19.1 in pluripotency or germ cell function we have generated Tex19.1(-/-) knockout mice and analysed the Tex19.1(-/-) mutant phenotype. Adult Tex19.1(-/-) knockout males exhibit impaired spermatogenesis. Immunostaining and histological analysis revealed defects in meiotic chromosome synapsis, the persistence of DNA double-strand breaks during meiosis, and a loss of post-meiotic germ cells in the testis. Furthermore, expression of a class of endogenous retroviruses is upregulated during meiosis in the Tex19.1(-/-) testes. Increased transposition of endogenous retroviruses in the germline of Tex19.1(-/-) mutant mice, and the concomitant increase in DNA damage, may be sufficient to disrupt the normal processes of recombination and chromosome synapsis during meiosis and cause defects in spermatogenesis. Our results suggest that Tex19.1 is part of a specialised mechanism that operates in the germline to repress transposable genetic elements and maintain genomic stability through successive generations.
Abstract
Some supernovae, such as pair-instability supernovae, are predicted to have a duration of more than a year in the observer frame. To constrain the rates of supernovae lasting for more than a ...year, we conducted a long-term deep transient survey using Hyper Suprime-Cam (HSC) on the 8.2 m Subaru telescope. HSC is a wide-field (a 1.75 deg
2
field-of-view) camera and it can efficiently conduct transient surveys. We observed the same 1.75 deg
2
field repeatedly using the
g-
,
r-
,
i-
, and
z-
band filters with the typical depth of 26 mag for four seasons (from late 2016 to early 2020). Using these data, we searched for transients lasting for more than a year. Two supernovae were detected in two continuous seasons, one supernova was detected in three continuous seasons, but no transients lasted for all four seasons searched. The discovery rate of supernovae lasting for more than a year with the typical limiting magnitudes of 26 mag is constrained to be
. All the long-lasting supernovae we found are likely Type IIn supernovae and our results indicate that about 40% of Type IIn supernovae have long-lasting light curves. No plausible pair-instability supernova candidates lasting for more than a year are discovered. By comparing the survey results and survey simulations, we constrain the luminous pair-instability supernova rate up to
z
≃ 3 is of the order of 100 Gpc
−3
yr
−1
at most, which is 0.01–0.1% of the core-collapse supernova rate.
Gametogenesis is a complex process subject to strict controls at both levels of transcription and translation. Members of a family of conserved RNA-binding proteins encoded by the DAZ genes are ...required for the translational regulation of gene expression essential for this process. Although loss of DAZ family genes is associated with infertility in several organisms including humans, the identity of the transcripts regulated in vivo is unknown. Using a combination of immunoprecipitation and microarray analysis, we have identified a number of mRNAs that are bound by the murine Dazl protein both in vivo and in vitro. Sequence analysis shows that these transcripts contain binding sites for Dazl, which have been conserved during evolution between human, rat and mouse. We have focussed on mouse vasa homologue (Mvh), a gene that is essential for male gametogenesis, and show that Dazl stimulates translation via the Mvh 3′-UTR. Finally, we show that germ cells of Dazl null mice contain reduced levels of Mvh protein, indicating that Dazl-mediated regulation of Mvh translation is crucial for mammalian spermatogenesis.
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