Restore or Redefine:Future Trajectories for Restoration

Global habitat deterioration of marine ecosystems has led to a need for active interventions to halt or reverse the loss of ecological function. Restoration has historically been a key tool to reverse habitat loss and restore functions, but the extent to which this will be sufficient under future climates is uncertain. Emerging genetic technologies now provide the ability for restoration to proactively match adaptability of target species to predicted future environmental conditions, which opens up the possibility of boosting resistance to future stress in degraded and threatened habitats. As such, the choice of whether to restore to historical baselines or anticipate the future remains a key decision that will influence restoration success in the face of environmental and climate change. Here, we present an overview of the different motives for restoration – to recover or revive lost or degraded habitats to extant or historical states, or to reinforce or redefine for future conditions. We focus on the genetic and adaptive choices that underpin each option and subsequent consequences for restoration success. These options span a range of possible trajectories, technological advances and societal acceptability, and represent a framework for progressing restoration of marine habitat forming species into the future

Simulating photodynamic therapy for the treatment of glioblastoma using Monte Carlo radiative transport

Funding: LF acknowledges financial support from the UK Research and Innovation (UKRI) Engineering and Physical Sciences Research Council (EPSRC) Centre for Doctoral Training in Applied Photonics (Grant No. EP/S022821/1) and the Laser Research and Therapy Fund (Grant No. SC030850).Significance Glioblastoma (GBM) is a rare but deadly form of brain tumor with a low median survival rate of 14.6 months, due to its resistance to treatment. An independent simulation of the INtraoperative photoDYnamic therapy for GliOblastoma (INDYGO) trial, a clinical trial aiming to treat the GBM resection cavity with photo- dynamic therapy (PDT) via a laser coupled balloon device, is demonstrated. Aim To develop a framework providing increased understanding for the PDT treatment, its parameters, and their impact on the clinical outcome. Approach We use Monte Carlo radiative transport techniques within a computational brain model containing a GBM to simulate light path and PDT effects. Treatment parameters (laser power, photosensitizer concentration, and irradiation time) are considered, as well as PDT’s impact on brain tissue temperature.  Results The simulation suggests that 39% of post-resection GBM cells are killed at the end of treatment when using the standard INDYGO trial protocol (light fluence = 200 J∕cm2 at balloon wall) and assuming an initial photosensitizer concentration of 5 μM. Increases in treatment time and light power (light fluence = 400 J∕cm2 at balloon wall) result in further cell kill but increase brain cell temperature, which potentially affects treatment safety. Increasing the p hotosensitizer concentration produces the most significant increase in cell kill, with 61% of GBM cells killed when doubling concentration to 10 μM and keeping the treatment time and power the same. According to these simulations, the standard trial protocol is reasonably well optimized with improvements in cell kill difficult to achieve without potentially dangerous increases in temperature. To improve treatment outcome, focus should be placed on improving the photosensitizer.  Conclusions With further development and optimization, the simulation could have potential clinical benefit and be used to help plan and optimize intraoperative PDT treatment for GBM.Peer reviewe

Coregulated human globin genes are frequently in spatial proximity when active

The organization of genes within the nucleus may influence transcription. We have analyzed the nuclear positioning of the coordinately regulated α- and β-globin genes and show that the gene-dense chromatin surrounding the human α-globin genes is frequently decondensed, independent of transcription. Against this background, we show the frequent juxtaposition of active α- and β-globin genes and of homologous α-globin loci that occurs at nuclear speckles and correlates with transcription. However, we did not see increased colocalization of signals, which would be expected with direct physical interaction. The same degree of proximity does not occur between human β-globin genes or between murine globin genes, which are more constrained to their chromosome territories. Our findings suggest that the distribution of globin genes within erythroblast nuclei is the result of a self-organizing process, involving transcriptional status, diffusional ability of chromatin, and physical interactions with nuclear proteins, rather than a directed form of higher-order control

Global gene expression analysis of human erythroid progenitors

This article is available open access through the publisher’s website. Copyright @ 2011 American Society of Hematology. This article has an erratum: http://bloodjournal.hematologylibrary.org/content/118/26/6993.3.Understanding the pattern of gene expression during erythropoiesis is crucial for a synthesis of erythroid developmental biology. Here, we isolated 4 distinct populations at successive erythropoietin-dependent stages of erythropoiesis, including the terminal, pyknotic stage. The transcriptome was determined using Affymetrix arrays. First, we demonstrated the importance of using defined cell populations to identify lineage and temporally specific patterns of gene expression. Cells sorted by surface expression profile not only express significantly fewer genes than unsorted cells but also demonstrate significantly greater differences in the expression levels of particular genes between stages than unsorted cells. Second, using standard software, we identified more than 1000 transcripts not previously observed to be differentially expressed during erythroid maturation, 13 of which are highly significantly terminally regulated, including RFXAP and SMARCA4. Third, using matched filtering, we identified 12 transcripts not previously reported to be continuously up-regulated in maturing human primary erythroblasts. Finally, using transcription factor binding site analysis, we identified potential transcription factors that may regulate gene expression during terminal erythropoiesis. Our stringent lists of differentially regulated and continuously expressed transcripts containing many genes with undiscovered functions in erythroblasts are a resource for future functional studies of erythropoiesis. Our Human Erythroid Maturation database is available at https://cellline.molbiol.ox.ac.uk/eryth/index.html.National Health Service Blood and Transplant, National Institute for Health Research Biomedical Research Center Program, and National Institute for Health Research

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Ethics, empathy and fear in research on violent conflict

The discussion of ethics in the social sciences focuses on ‘doing no harm’ and ‘giving back’ to research participants, but does not explore the challenges of empathy and fear in research with participants in political violence and war. Drawing on 180 in-depth interviews on the Georgian-Abkhaz war of 1992-1993 collected over eight months between 2010 and 2013 primarily in Abkhazia, but also Georgia and Russia, I argue that researchers can come to empathize with some but fear other participants in past and present violence. These emotional responses can influence researchers’ ability to probe and interpret interviews and respondents’ ability to surpass strong positions to explore dilemmas of participation in violence. By empathizing with not only ‘victims’ and ‘non-fighters’ as I had expected based on my pre-existing moral-conceptual categories, but also participants in the war, I found that individuals adopted multiple overlapping roles and shifted between these roles in the changing conditions of violence. In contrast, failing to empathize with and fearing those who continued to participate in violence at the time of my interviews limited my ability to fully appreciate the complexity of their participation, but shed light on the context of violence in contemporary Abkhazia. This analysis shows that reflection on the role of empathy and fear in shaping our interactions with research participants can help advance our understanding of participation in violence and this difficult research context

Upscaling marine forest restoration: challenges, solutions and recommendations from the Green Gravel Action Group

IntroductionTo counteract the rapid loss of marine forests globally and meet international commitments of the UN Decade on Ecosystem Restoration and the Convention on Biological Diversity ‘30 by 30’ targets, there is an urgent need to enhance our capacity for macroalgal restoration. The Green Gravel Action Group (GGAG) is a global network of 67 members that are working on the restoration of a diverse range of macroalgal forests and it aims to facilitate knowledge exchange to fast-track innovation and implementation of outplanting approaches worldwide. MethodsHere, we overview 25 projects conducted by members of the group that are focused on testing and developing techniques for macroalgal restoration. Based on these projects, we summarise the major challenges associated with scaling up the area of marine forests restored. ResultsWe identify several critical challenges that currently impede more widespread rollout of effective large-scale macroalgal restoration worldwide: 1) funding and capacity limitations, 2) difficulties arising from conditions at restoration sites, 3) technical barriers, and 4) challenges at the restoration-policy interface. DiscussionDespite these challenges, there has been substantial progress, with an increasing number of efforts, community engagement and momentum towards scaling up activities in recent years. Drawing on the collective expertise of the GGAG, we outline key recommendations for the scaling up of restoration efforts to match the goals of international commitments. These include the establishment of novel pathways to fund macroalgal restoration activities, building skills and capacity, harnessing emerging innovations in mobile hatchery and seeding technologies, and the development of the scientific and governance frameworks necessary to implement and monitor macroalgal restoration projects at scale

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies