BHLHE40 regulates the T-cell effector function required for tumor microenvironment remodeling and immune checkpoint therapy efficacy

Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell-dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti-PD-1 and anti-CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor antigen-specific CD8+ and CD4+ T cells and that T cells require BHLHE40 for effective ICT in mice bearing immune-edited tumors. Single-cell RNA sequencing of intratumoral immune cells in BHLHE40-deficient mice revealed differential ICT-induced immune cell remodeling. The BHLHE40-dependent gene expression changes indicated dysregulated metabolism, NF-κB signaling, and IFNγ response within certain subpopulations of CD4+ and CD8+ T cells. Intratumoral CD4+ and CD8+ T cells from BHLHE40-deficient mice exhibited higher expression of the inhibitory receptor gene Tigit and displayed alterations in expression of genes encoding chemokines/chemokine receptors and granzyme family members. Mice lacking BHLHE40 had reduced ICT-driven IFNγ production by CD4+ and CD8+ T cells and defects in ICT-induced remodeling of macrophages from a CX3CR1+CD206+ subpopulation to an iNOS+ subpopulation that is typically observed during effective ICT. Although both anti-PD-1 and anti-CTLA-4 ICT in BHLHE40-deficient mice led to the same outcome-tumor outgrowth-several BHLHE40-dependent alterations were specific to the ICT that was used. Our results reveal a crucial role for BHLHE40 in effective ICT and suggest that BHLHE40 may be a predictive or prognostic biomarker for ICT efficacy and a potential therapeutic target

RELICS: Strong Lens Models for Five Galaxy Clusters From the Reionization Lensing Cluster Survey

Strong gravitational lensing by galaxy clusters magnifies background galaxies, enhancing our ability to discover statistically significant samples of galaxies at z>6, in order to constrain the high-redshift galaxy luminosity functions. Here, we present the first five lens models out of the Reionization Lensing Cluster Survey (RELICS) Hubble Treasury Program, based on new HST WFC3/IR and ACS imaging of the clusters RXC J0142.9+4438, Abell 2537, Abell 2163, RXC J2211.7-0349, and ACT-CLJ0102-49151. The derived lensing magnification is essential for estimating the intrinsic properties of high-redshift galaxy candidates, and properly accounting for the survey volume. We report on new spectroscopic redshifts of multiply imaged lensed galaxies behind these clusters, which are used as constraints, and detail our strategy to reduce systematic uncertainties due to lack of spectroscopic information. In addition, we quantify the uncertainty on the lensing magnification due to statistical and systematic errors related to the lens modeling process, and find that in all but one cluster, the magnification is constrained to better than 20% in at least 80% of the field of view, including statistical and systematic uncertainties. The five clusters presented in this paper span the range of masses and redshifts of the clusters in the RELICS program. We find that they exhibit similar strong lensing efficiencies to the clusters targeted by the Hubble Frontier Fields within the WFC3/IR field of view. Outputs of the lens models are made available to the community through the Mikulski Archive for Space TelescopesComment: Accepted to Ap

RELICS: High-Resolution Constraints on the Inner Mass Distribution of the z=0.83 Merging Cluster RXJ0152.7-1357 from strong lensing

Strong gravitational lensing (SL) is a powerful means to map the distribution of dark matter. In this work, we perform a SL analysis of the prominent X-ray cluster RXJ0152.7-1357 (z=0.83, also known as CL 0152.7-1357) in \textit{Hubble Space Telescope} images, taken in the framework of the Reionization Lensing Cluster Survey (RELICS). On top of a previously known $z=3.93$ galaxy multiply imaged by RXJ0152.7-1357, for which we identify an additional multiple image, guided by a light-traces-mass approach we identify seven new sets of multiply imaged background sources lensed by this cluster, spanning the redshift range [1.79-3.93]. A total of 25 multiple images are seen over a small area of ~0.4 $arcmin^2$, allowing us to put relatively high-resolution constraints on the inner matter distribution. Although modestly massive, the high degree of substructure together with its very elongated shape make RXJ0152.7-1357 a very efficient lens for its size. This cluster also comprises the third-largest sample of z~6-7 candidates in the RELICS survey. Finally, we present a comparison of our resulting mass distribution and magnification estimates with those from a Lenstool model. These models are made publicly available through the MAST archive.Comment: 15 Pages, 7 Figures, 4 Tables Accepted for publication in Ap

Mapping opportunities and challenges for rewilding in Europe

Farmland abandonment takes place across the world due to socio-economic and ecological drivers. In Europe agricultural and environmental policies aim to prevent abandonment and halt ecological succession. Ecological rewilding has been recently proposed as an alternative strategy. We developed a framework to assess opportunities for rewilding across different dimensions of wilderness in Europe. We mapped artificial light, human accessibility based on transport infrastructure, proportion of harvested primary productivity (i.e., ecosystem productivity appropriated by humans through agriculture or forestry), and deviation from potential natural vegetation in areas projected to be abandoned by 2040. At the continental level, the levels of artificial light were low and the deviation from potential natural vegetation was high in areas of abandonment. The relative importance of wilderness metrics differed regionally and was strongly connected to local environmental and socio-economic contexts. Large areas of projected abandonment were often located in or around Natura 2000 sites. Based on these results, we argue that management should be tailored to restore the aspects of wilderness that are lacking in each region. There are many remaining challenges regarding biodiversity in Europe, but megafauna species are already recovering. To further potentiate large-scale rewilding, Natura 2000 management would need to incorporate rewilding approaches. Our framework can be applied to assessing rewilding opportunities and challenges in other world regions, and our results could guide redirection of subsidies to manage social-ecological systems

RELICS: A Strong Lens Model for SPT-CLJ0615-5746, a z=0.972 Cluster

We present a lens model for the cluster SPT-CLJ0615$-$5746, which is the highest redshift ($z=0.972$) system in the Reionization of Lensing Clusters Survey (RELICS), making it the highest redshift cluster for which a full strong lens model is published. We identify three systems of multiply-imaged lensed galaxies, two of which we spectroscopically confirm at $z=1.358$ and $z=4.013$, which we use as constraints for the model. We find a foreground structure at $z\sim0.4$, which we include as a second cluster-sized halo in one of our models; however two different statistical tests find the best-fit model consists of one cluster-sized halo combined with three individually optimized galaxy-sized halos, as well as contributions from the cluster galaxies themselves. We find the total projected mass density within $r=26.7"$ (the region where the strong lensing constraints exist) to be $M=2.51^{+0.15}_{-0.09}\times 10^{14}$~M$_{\odot}$. If we extrapolate out to $r_{500}$, our projected mass density is consistent with the mass inferred from weak lensing and from the Sunyaev-Zel'dovich effect ($M\sim10^{15}$~M$_{\odot}$). This cluster is lensing a previously reported $z\sim10$ galaxy, which, if spectroscopically confirmed, will be the highest-redshift strongly lensed galaxy known.Comment: 15 pages, 8 figures 4 tables. ApJ Accepte

RELICS: The Reionization Lensing Cluster Survey and the Brightest High-z Galaxies

Massive foreground galaxy clusters magnify and distort the light of objects behind them, permitting a view into both the extremely distant and intrinsically faint galaxy populations. We present here the z ~ 6-8 candidate high-redshift galaxies from the Reionization Lensing Cluster Survey (RELICS), a Hubble and Spitzer Space Telescope survey of 41 massive galaxy clusters spanning an area of ≈200 arcmin². These clusters were selected to be excellent lenses, and we find similar high-redshift sample sizes and magnitude distributions as the Cluster Lensing And Supernova survey with Hubble (CLASH). We discover 257, 57, and eight candidate galaxies at z ~ 6, 7, and 8 respectively, (322 in total). The observed (lensed) magnitudes of the z ~ 6 candidates are as bright as AB mag ~23, making them among the brightest known at these redshifts, comparable with discoveries from much wider, blank-field surveys. RELICS demonstrates the efficiency of using strong gravitational lenses to produce high-redshift samples in the epoch of reionization. These brightly observed galaxies are excellent targets for follow-up study with current and future observatories, including the James Webb Space Telescope

Persistent frequent attenders in primary care: costs, reasons for attendance, organisation of care and potential for cognitive behavioural therapeutic intervention

<p><b>Abstract</b></p> <p>Background</p> <p>The top 3% of frequent attendance in primary care is associated with 15% of all appointments in primary care, a fivefold increase in hospital expenditure, and more mental disorder and functional somatic symptoms compared to normal attendance. Although often temporary if these rates of attendance last more than two years, they may become persistent (persistent frequent or regular attendance). However, there is no long-term study of the economic impact or clinical characteristics of regular attendance in primary care. Cognitive behaviour formulation and treatment (CBT) for regular attendance as a motivated behaviour may offer an understanding of the development, maintenance and treatment of regular attendance in the context of their health problems, cognitive processes and social context.</p> <p>Methods/design</p> <p>A case control design will compare the clinical characteristics, patterns of health care use and economic costs over the last 10 years of 100 regular attenders (≥30 appointments with general practitioner [GP] over 2 years) with 100 normal attenders (6–22 appointments with GP over 2 years), from purposefully selected primary care practices with differing organisation of care and patient demographics. Qualitative interviews with regular attending patients and practice staff will explore patient barriers, drivers and experiences of consultation, and organisation of care by practices with its challenges. Cognitive behaviour formulation analysed thematically will explore the development, maintenance and therapeutic opportunities for management in regular attenders. The feasibility, acceptability and utility of CBT for regular attendance will be examined.</p> <p>Discussion</p> <p>The health care costs, clinical needs, patient motivation for consultation and organisation of care for persistent frequent or regular attendance in primary care will be explored to develop training and policies for service providers. CBT for regular attendance will be piloted with a view to developing this approach as part of a multifaceted intervention.</p

RELICS: A Very Large (θE∼40"\theta_{E}\sim40") Cluster Lens -- RXC J0032.1+1808

Extensive surveys with the \textit{Hubble Space Telescope} (HST) over the past decade, targeting some of the most massive clusters in the sky, have uncovered dozens of galaxy-cluster strong lenses. The massive cluster strong-lens scale is typically \theta_{E}\sim10\arcsec to \sim30-35\arcsec, with only a handful of clusters known with Einstein radii \theta_{E}\sim40\arcsec or above (for $z_{source}=2$, nominally). Here we report another very large cluster lens, RXC J0032.1+1808 ($z=0.3956$), the second richest cluster in the redMapper cluster catalog and the 85th most massive cluster in the Planck Sunyaev-Zel'dovich catalog. With our Light-Traces-Mass and fully parametric (dPIEeNFW) approaches, we construct strong lensing models based on 18 multiple images of 5 background galaxies newly identified in the \textit{Hubble} data mainly from the \textit{Reionization Lensing Cluster Survey} (RELICS), in addition to a known sextuply imaged system in this cluster. Furthermore, we compare these models to Lenstool and GLAFIC models that were produced independently as part of the RELICS program. All models reveal a large effective Einstein radius of \theta_{E}\simeq40\arcsec ($z_{source}=2$), owing to the obvious concentration of substructures near the cluster center. Although RXC J0032.1+1808 has a very large critical area and high lensing strength, only three magnified high-redshift candidates are found within the field targeted by RELICS. Nevertheless, we expect many more high-redshift candidates will be seen in wider and deeper observations with \textit{Hubble} or \emph{JWST}. Finally, the comparison between several algorithms demonstrates that the total error budget is largely dominated by systematic uncertainties.Comment: 23 pages, accepted for publication in Ap

Rapid Chromosome Evolution in Recently Formed Polyploids in Tragopogon (Asteraceae)

Polyploidy, frequently termed "whole genome duplication", is a major force in the evolution of many eukaryotes. Indeed, most angiosperm species have undergone at least one round of polyploidy in their evolutionary history. Despite enormous progress in our understanding of many aspects of polyploidy, we essentially have no information about the role of chromosome divergence in the establishment of young polyploid populations. Here we investigate synthetic lines and natural populations of two recently and recurrently formed allotetraploids Tragopogon mirus and T. miscellus (formed within the past 80 years) to assess the role of aberrant meiosis in generating chromosomal/genomic diversity. That diversity is likely important in the formation, establishment and survival of polyploid populations and species.Applications of fluorescence in situ hybridisation (FISH) to natural populations of T. mirus and T. miscellus suggest that chromosomal rearrangements and other chromosomal changes are common in both allotetraploids. We detected extensive chromosomal polymorphism between individuals and populations, including (i) plants monosomic and trisomic for particular chromosomes (perhaps indicating compensatory trisomy), (ii) intergenomic translocations and (iii) variable sizes and expression patterns of individual ribosomal DNA (rDNA) loci. We even observed karyotypic variation among sibling plants. Significantly, translocations, chromosome loss, and meiotic irregularities, including quadrivalent formation, were observed in synthetic (S(0) and S(1) generations) polyploid lines. Our results not only provide a mechanism for chromosomal variation in natural populations, but also indicate that chromosomal changes occur rapidly following polyploidisation.These data shed new light on previous analyses of genome and transcriptome structures in de novo and establishing polyploid species. Crucially our results highlight the necessity of studying karyotypes in young (<150 years old) polyploid species and synthetic polyploids that resemble natural species. The data also provide insight into the mechanisms that perturb inheritance patterns of genetic markers in synthetic polyploids and populations of young natural polyploid species