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Mammalian heart development requires precise allocation of cardiac progenitors. The existence of a multipotent progenitor for all anatomic and cellular components of the heart has been predicted but its identity and contribution to the two cardiac progenitor ‘fields’ has remained undefined. Here we show, using clonal genetic fate mapping, that Mesp1+ cells in gastrulating mesoderm are rapidly specified into committed cardiac precursors fated for distinct anatomic regions of the heart. We identify Smarcd3 as a marker of early specified cardiac precursors and identify within these precursors a compartment boundary at the future junction of the left and right ventricles that arises prior to morphogenesis. Our studies define the timing and hierarchy of cardiac progenitor specification and demonstrate that the cellular and anatomical fate of mesoderm-derived cardiac cells is specified very early. These findings will be important to understand the basis of congenital heart defects and to derive cardiac regeneration strategies. Most internal organs in the body are made up of several different kinds of cells. Understanding where these cells come from and how these different cells develop from a single cell in an embryo could help to guide regenerative therapies, where tissues grown in the laboratory are used to repair damage that the body cannot repair itself. The existence of a single heart progenitor cell that can produce all of the heart's structures has long been predicted, but has so far escaped discovery. Currently, it is known that two distinct sets of heart precursor cells exist in mammals, which each produce cells for different parts of the heart. Work performed in mouse embryos has hinted that both sets of cells develop from cells that produce a protein called Mesp1. This protein controls when many genes—including those involved in heart development—are activated. Devine et al. marked a small number of Mesp1-producing cells and followed the fate of these cells through development to see where their descendants would end up within the embryo—and specifically within the mature heart. Labeling occurred at a very early stage of development, called gastrulation, when the embryonic cells first begin to organize themselves into three tissue layers that will go on to form all the different parts of the organism. Devine et al. found that shortly after gastrulation begins, heart precursor cells are present and are already assigned to particular regions of the heart. This means that if there is a single pool of heart precursor cells, it specializes into different populations very early in the development of an embryo. Devine et al. show that during gastrulation, heart precursor cells are already split into two distinct populations: one containing the cells that go on to form the atria and left ventricle of the heart; the other consisting of the cells that will make up the right ventricle and the ‘outflow tract’ that will eventually form the great vessels leading into and out of the heart. These two populations are separated by a boundary, which Devine et al. suggest is established very early on, and will go on to form the septum that separates the left and right ventricles in the developed heart. As defects in the septum are the source of many congenital heart defects, a better understanding of the heart cell precursor populations and how they interact could help develop treatments for these conditions.

In patients who have, or are at risk for, coronary artery disease, niacin added to statin therapy resulted in regression of the carotid intima–media thickness. In contrast, ezetimibe added to statin therapy paradoxically resulted in progression of the carotid intima–media thickness. Treatment with 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors reduces low-density lipoprotein (LDL) cholesterol levels and results in clinically significant reductions in the relative risk of major cardiovascular events. 1 However, because of the residual cardiovascular risk seen with statin monotherapy, treatment may be intensified with the use of combination therapy, aimed at either further reducing the LDL cholesterol level or at altering levels of other lipids, such as high-density lipoprotein (HDL) cholesterol. Progressive lowering of the LDL cholesterol level through intensification of statin therapy leads to a 16% reduction in the odds of cardiovascular events and death from cardiovascular causes. 2 This approach has . . .

Scepticism about the value of parochialism and local belonging has been a persistent feature of geographical scholarship, which has advocated a relational account of place and a cosmopolitan worldview. This paper revisits the Parish Maps project that was instigated in 1987 by UK arts and environment charity Common Ground, which led to the creation of thousands of maps across the UK and beyond, and was appraised in 1996 by Crouch and Matless in this journal. Drawing on archival materials and in-depth interviews, we examine the legacy of the project. We argue that Common Ground's vision for Parish Maps represents a \"positive parochialism\" that confidently asserts the validity of the parish without retreating towards insularity. We complicate this by revealing diverse ways that communities took up Common Ground's vision. We conclude by arguing that the view of parochialism manifest by Parish Maps offers a foundation for ecological concern that remains relevant today, with places offering the potential for solidarities that bring together local and incomer. This \"positive parochialism\" disturbs assumptions that local attachments are necessarily exclusive and indicates the unresolved challenge of finding ways to realise the value of affect and creative environmental engagement in wider policy and land-use planning.

Throughout the world, the threat of climate change is pressing governments to accelerate the deployment of technologies to generate low carbon electricity or heat. But this is frequently leading to controversy, as energy and planning policies are revised to support new energy sources or technologies (e.g. offshore wind, tidal, bioenergy or hydrogen energy) and communities face the prospect of unfamiliar, often large-scale energy technologies being sited near to their homes. Policy makers in many countries face tensions between 'streamlining' planning procedures, engaging with diverse publics to address what is commonly conceived as 'NIMBY' (not in my back yard) opposition, and the need to maintain democratic, participatory values in planning systems. This volume provides a timely, international review of research on public engagement, in contexts of diverse, innovative energy technologies. Public engagement is conceived broadly - as the interaction between how developers and other key actors engage with publics about energy technologies (including assumptions held about the methods used, such as the provision of financial benefits or the holding of deliberative events), and how individuals and groups engage with energy policies and projects (including indirectly through the media and directly through emotional and behavioural responses). The book's contributors are leading experts in the UK, Europe, North and South America and Australia drawn from a variety of relevant social science disciplinary perspectives. The book makes a significant contribution to our existing knowledge, as well as providing interested professionals, policymakers and members of the public with a timely overview of the critical issues involved in public engagement with low carbon energy technologies.

1. The spatial distributions of biodiversity and people vary across landscapes and are critical to the delivery of ecosystem services and disservices. The high densities of people and often of birds in urban areas lead to frequent human-avian interactions, which can be positive or negative for people's well-being. The identities of the bird species providing these services or disservices tend to be quite different; however, it is unclear how their abundance and richness covary with human population density, and hence with potential recipients of these services and disservices. 2. We surveyed bird populations in 106 tiles (500 × 500 m) across the 174 km² of an extended urban area in southern England. From the literature, we identified two groups of species: those associated with positive interactions for human well-being and those that display behaviours that are negative for human well-being. We estimated the abundance (adjusted for detection probability) and richness of each group and modelled how they covary with human population density. 3. Aggregation of population estimates for the 35 service and nine disservice species observed revealed 593,128 (95% confidence interval: 541,817-657,046) and 225,491 (200,134-235,066) birds respectively. Across the surveyed tiles, there were 1.09 service and 0.42 disservice birds per person. 4. There was a peaking quadratic relationship between service abundance and human population density, but a negative linear relationship between richness and human density. Conversely, there were positive linear relationships for both abundance and richness of disservice species with human density. The ratio of service to disservice birds shifted from 3.5-1 at intermediate human densities to 1-1 in more densely populated areas. 5. Synthesis and applications. Differences in the distributions of service and disservice species, and the extremely low ratios of birds to people particularly in socioeconomically deprived areas, mean that people there have few opportunities for contact with birds, and the contact they do have is equally likely to be negative as positive for human well-being. We recommend spatial targeting of improvements in green infrastructure, combined with the targeted provisioning of food and nesting places for service species, to promote positive interactions between birds and people.

During the phylotypic period, embryos from different genera show similar gene expression patterns, implying common regulatory mechanisms. Here we set out to identify enhancers involved in the initial events of cardiogenesis, which occurs during the phylotypic period. We isolate early cardiac progenitor cells from zebrafish embryos and characterize 3838 open chromatin regions specific to this cell population. Of these regions, 162 overlap with conserved non-coding elements (CNEs) that also map to open chromatin regions in human. Most of the zebrafish conserved open chromatin elements tested drive gene expression in the developing heart. Despite modest sequence identity, human orthologous open chromatin regions recapitulate the spatial temporal expression patterns of the zebrafish sequence, potentially providing a basis for phylotypic gene expression patterns. Genome-wide, we discover 5598 zebrafish-human conserved open chromatin regions, suggesting that a diverse repertoire of ancient enhancers is established prior to organogenesis and the phylotypic period. During early embryogenesis, critical cardiac specification events occur. Here the authors isolate cardiac progenitor cells from early zebrafish embryos and characterize accessible chromatin regions specific to this cell population, finding that many of these regions overlap with conserved non-coding elements that are ortholgous to accessible chromatin regions in human.

Decarbonizing industrial sectors is a critical global challenge, involving the creation of new industrial spaces—‘net zero industrial clusters’—co‐locating energy sectors and ‘hard‐to‐abate’ industries such as oil refining and steelmaking. This paper provides the first empirically grounded geographical investigation of these emerging spaces. It employs a place‐based research agenda to unpack how UK net zero industrial clusters (ICs) are imagined and emplaced in policy and industry discourses through place‐based naming, spatial configuring and mapping activities. By conducting document analysis, 33 in‐depth stakeholder interviews and five field trips to three UK case studies, we show how cluster imaginaries vary across cases and policy contexts in terms of constituents, focus and purpose. Ontological complexity is compounded by different rationales among stakeholders in configuring clusters and by contested cluster naming and boundary setting. This ambiguous, evolving spatiality raises important political and justice concerns over who and where is excluded in cluster building. These findings advance the geographies of low‐carbon transitions by showing: (1) ways that ICs' spatial embeddedness, which underlies cluster spatial configurations, helps increase industry actors' recognition of their economic, social and cultural ties with the places of their making, even if this risks path dependency; (2) how fluid cluster boundaries, reflected in cluster names and maps, emphasize the value of a network topology of scale to enable spatially inclusive, multi‐scalar climate mitigation. Finally, we argue that a place‐sensitive net zero policy mindset is vital for fulfilling ICs and the UK's decarbonization potential in a manner that is both fair and locally grounded. Short This paper employed a place‐based research agenda to investigate new industrial spaces (proposed to be) created by/for industrial decarbonization, with a special focus on the imagining and emplacement of net zero industrial clusters in UK policy and industry discourses. It advances a more sophisticated reading of spatial embeddedness and (re)scaling in the multi‐sector transition process, including their implications for just transitions and the importance of a network topology of scale in accelerating an inclusive climate mitigation. It argues that a place‐sensitive net zero policy mindset is vital for fulfilling ICs and the UK's decarbonization potential in a manner that is both fair and locally grounded.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.

Sequencing data have been instrumental in identifying oncogenic drivers in prostatic carcinoma and highlighting biomarkers that define aggressive disease. A review of a series of 30 primary and metastatic prostatic carcinomas clinically sequenced at our cancer genomics laboratory utilizing a targeted gene panel identified recurrent structural variants in the TP53 gene. These structural variants were found in 27% of all sequenced cases and represented 36% of the cases with metastatic disease. TP53 structural rearrangements have been previously reported in a significant subset of osteosarcomas, where they result in loss of p53 protein expression by immunohistochemistry. Similarly, in our prostate cases with TP53 structural rearrangements for which tissue was available for testing, we find loss of p53 protein expression by immunohistochemistry. In the eight TP53-rearranged cases, concurrent PTEN loss was identified in 4 cases, TMPRSS2-ERG fusion in 5 cases, and AR and FOXA1 amplification in 1 case each. Our results from this small case series suggest that TP53 rearrangements with loss of expression represent a frequent alternative mechanism of inactivation of this key tumor suppressor gene with potential utility as a marker of aggressive disease. Recognition of this TP53 rearrangement pathway is essential to accurately identify prostatic carcinomas with loss of TP53 function.

Evidence of T-cell clonality is often critical in supporting the diagnosis of a T-cell lymphoma. To retrospectively explore the significance of copy number losses at the 14q11.2 T-cell receptor α locus in relation to the presence of a T-cell neoplasm and proportion of T cells by targeted next-generation sequencing. Targeted next-generation sequencing data from 139 tissue biopsies, including T-cell lymphomas, B-cell lymphomas, classic Hodgkin lymphomas, nonhematopoietic malignancies, and normal samples, were reviewed for copy number losses involving the T-cell receptor α gene segments at chr14q11.2. We found that biallelic or homozygous deletion of 14q11.2 was found in most (28 of 33, 84.8%) T-cell lymphomas. The magnitude of 14q11.2 loss showed a statistically significant correlation with the proportion of T cells in lymphoma tissue samples. Copy number losses could also be detected in other lymphomas with high numbers of T cells (8 of 32, 25% of B-cell lymphomas, 4 of 4 classical Hodgkin lymphomas), though biallelic/homozygous deletion of 14q11.2 was not significantly observed outside of T-cell lymphomas. Most nonhematopoietic neoplasms and normal tissues (59 of 64, 92.2%) showed no significant copy number losses involving the T-cell receptor α locus at chr14q11.2. Analysis of copy number losses at the T-cell receptor α locus chr14q11.2 with targeted next-generation sequencing can potentially be used to estimate the proportion of T cells and detect T-cell neoplasms.