Limited antigenic diversity of Plasmodium falciparum apical membrane antigen 1 supports the development of effective multi-allele vaccines

BackgroundPolymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies.MethodsWe aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence.ResultsWe found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis.ConclusionsAntigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines

Preventable deaths involving opioids in England and Wales, 2013–2022: a systematic case series of coroners’ reports

Background Opioid deaths have increased in England and Wales. Coroners’ Prevention of Future Deaths reports (PFDs) provide important insights that may enable safer use and avert harms, yet reports implicating opioids have not been synthesized. We aimed to identify opioid-related PFDs and explore coroners’ concerns to prevent future deaths. Methods In this systematic case series, we screened 3897 coronial PFDs dated between 01 July 2013 and 23 February 2022, obtained by web scraping the UK’s Courts and Tribunals Judiciary website. PFDs were included when an opioid was implicated in the death. Included PFDs were descriptively analysed, and content analysis was used to assess concerns reported by coroners. Results Opioids were involved in 219 deaths reported in PFDs (5·6% of PFDs), equating to 4418 years of life lost (median 33 years/person). Morphine (29%), methadone (23%) and diamorphine (16%) were the most common implicated opioids. Coroners most frequently raised concerns regarding systems and protocols (52%) or safety issues (15%). These concerns were most often addressed to National Health Service (NHS) organizations (51%), but response rates were low overall (47%). Conclusions Opioids could be used more safely if coroners’ concerns in PFDs were addressed by national organizations such as NHS bodies, government agencies and policymakers, as well as individual prescribing clinicians

Identifying High Metallicity M Giants at Intragroup Distances with SDSS

Tidal stripping and three-body interactions with the central supermassive black hole may eject stars from the Milky Way. These stars would comprise a set of `intragroup' stars that trace the past history of interactions in our galactic neighborhood. Using the Sloan Digital Sky Survey DR7, we identify candidate solar metallicity red giant intragroup stars using color cuts that are designed to exclude nearby M and L dwarfs. We present 677 intragroup candidates that are selected between 300 kpc and 2 Mpc, and are either the reddest intragroup candidates (M7-M10) or are L dwarfs at larger distances than previously detected.Comment: 8 pages, 6 figures, 1 table (for full version, see http://astro.phy.vanderbilt.edu/~palladl2), Accepted for publication in A

The structure of the caspase recruitment domain of BinCARD reveals that all three cysteines can be oxidized

The caspase recruitment domain (CARD) is present in death-domain superfamily proteins involved in inflammation and apoptosis. BinCARD is named for its ability to interact with Bcl10 and inhibit downstream signalling. Human BinCARD is expressed as two isoforms that encode the same N-terminal CARD region but which differ considerably in their C-termini. Both isoforms are expressed in immune cells, although BinCARD-2 is much more highly expressed. Crystals of the CARD fold common to both had low symmetry (space group P1). Molecular replacement was unsuccessful in this low-symmetry space group and, as the construct contains no methionines, first one and then two residues were engineered to methionine for MAD phasing. The double-methionine variant was produced as a selenomethionine derivative, which was crystallized and the structure was solved using data measured at two wavelengths. The crystal structures of the native and selenomethionine double mutant were refined to high resolution (1.58 and 1.40 Å resolution, respectively), revealing the presence of a cis-peptide bond between Tyr39 and Pro40. Unexpectedly, the native crystal structure revealed that all three cysteines were oxidized. The mitochondrial localization of BinCARD-2 and the susceptibility of its CARD region to redox modification points to the intriguing possibility of a redox-regulatory role

Combining Enzalutamide with Abiraterone, Prednisone, and Androgen Deprivation Therapy in the STAMPEDE Trial

There are compelling reasons to study the addition of both enzalutamide and abiraterone, in combination, to standard-of-care for hormone-naïve prostate cancer. Through a protocol amendment, this will be assessed in the STAMPEDE trial, with overall survival as primary outcome measure. © 2014 European Association of Urology

Gene content evolution in the arthropods

Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity

X-linked microtubule-associated protein, Mid1, regulates axon development

Opitz syndrome (OS) is a genetic neurological disorder. The gene responsible for the X-linked form of OS, Midline-1 (MID1), encodes an E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). However, how Mid1 functions during neural development is largely unknown. In this study, we provide data from in vitro and in vivo experiments suggesting that silencing Mid1 in developing neurons promotes axon growth and branch formation, resulting in a disruption of callosal axon projections in the contralateral cortex. In addition, a similar phenotype of axonal development was observed in the Mid1 knockout mouse. This defect was largely due to the accumulation of PP2Ac in Mid1-depleted cells as further down-regulation of PP2Ac rescued the axonal phenotype. Together, these data demonstrate that Mid1-dependent PP2Ac turnover is important for normal axonal development and that dysregulation of this process may contribute to the underlying cause of OS

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version

The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey

The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T_eff<5000 K and in metallicity estimates for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SDSS-III Sloan Extension for Galactic Understanding and Exploration-2 (SEGUE-2). The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) along with another year of data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at http://www.sdss3.org/dr

The use of surgery in the treatment of ER+ early stage breast cancer in England: variation by time, age and patient characteristics

AIM: To assess whether the proportion of patients aged 70 and over with ER+ operable breast cancer in England who are treated with surgery has changed since 2002, and to determine whether age and individual level factors including tumour characteristics and co-morbidity influence treatment choice. METHODS: A retrospective cohort analysis of routinely collected cancer registration data from two English regions (West Midlands, Northern & Yorkshire) was carried out (n = 17,129). Trends in surgical use over time for different age groups were assessed graphically and with linear regression. Uni- and multivariable logistic regressions were used to assess the effects of age, comorbidity, deprivation and disease characteristics on treatment choice. Missing data was handled using multiple imputation. RESULTS: There is no evidence of a change in the proportion of patients treated surgically over time. The multivariable model shows that age remains an important predictor of whether or not a woman with ER+ operable breast cancer receives surgery after covariate adjustment (Odds ratio of surgery vs no surgery, 0.82 (per year over 70)). Co-morbidity, deprivation, symptomatic presentation, later stage at diagnosis and low grade are also associated with increased probability of non-surgical treatment. CONCLUSION: Contrary to current NICE guidance in England, age appears to be an important factor in the decision to treat operable ER+ breast cancer non-surgically. Further research is needed to assess the role of other age-related factors on treatment choice, and the effect that current practice has on survival and mortality from breast cancer for older women