Charcoal, predominantly the product of wildfires, is abundant in many sedimentary rocks deposited in a wide range of environments, from terrestrial to marine. It also occurs in some volcanic rocks. ...This paper outlines aspects of charcoal formation (both natural and experimental) and briefly considers the taphonomic processes leading to a final assemblage. This is done using examples from recent fires and through experimentation. The ways in which charcoal assemblages are recognized in the field and extraction in the laboratory are also considered. Methods of charcoal identification are presented. The range of charcoalified plant organs that can be found is discussed and a wide range of study methods outlined (including light microscopy, dark field light microscopy, reflectance microscopy, scanning electron microscopy and synchrotron radiation X-ray tomographic microscopy). Emphasis in this paper is on the study of macro- and meso-charcoal (above180
µm). Finally there is a consideration of the broad use of charcoal from plant evolution studies, fire history studies, vegetation studies, anatomical studies, climate and atmospheric studies and the wider importance of charcoal for the Earth and Biological Sciences. Charcoal is information rich but yet is an under-utilized resource.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Several studies have documented fish populations changing in response to long-term warming. Over the past decade, sea surface temperatures in the Gulf of Maine increased faster than 99% of the global ...ocean. The warming, which was related to a northward shift in the Gulf Stream and to changes in the Atlantic Multidecadal Oscillation and Pacific Decadal Oscillation, led to reduced recruitment and increased mortality in the region's Atlantic cod (Gadus morhua) stock. Failure to recognize the impact of warming on cod contributed to overfishing. Recovery of this fishery depends on sound management, but the size of the stock depends on future temperature conditions. The experience in the Gulf of Maine highlights the need to incorporate environmental factors into resource management.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune ...checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1
dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1
tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, ...biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples—at three hot spots and 13 minor sites—and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.
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•ALK mutations occur in 8% of neuroblastoma patients across all stages of disease•The presence of an ALK tyrosine kinase domain mutation correlates with poor prognoses•A biochemically informed computational approach identifies oncogenic mutations•Oncogenic ALK mutations differ significantly in tumor cell sensitivity to crizotinib
Bresler et al. carry out comprehensive genomic, biochemical, and computational analyses of ALK mutations across a large cohort of diagnostic neuroblastoma samples and develop computational approaches for identifying disease-significant ALK mutations, which will also allow tailoring of ALK-targeted therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Solid-state quantum acoustodynamic (QAD) systems provide a compact platform for quantum information storage and processing by coupling acoustic phonon sources with superconducting or spin qubits. The ...multi-mode composite high-overtone bulk acoustic wave resonator (HBAR) is a popular phonon source well suited for QAD. However, scattering from defects, grain boundaries, and interfacial/surface roughness in the composite transducer severely limits the phonon relaxation time in sputter-deposited devices. Here, we grow an epitaxial-HBAR, consisting of a metallic NbN bottom electrode and a piezoelectric GaN film on a SiC substrate. The acoustic impedance-matched epi-HBAR has a power injection efficiency >99% from transducer to phonon cavity. The smooth interfaces and low defect density reduce phonon losses, yielding (f × Q) and phonon lifetimes up to 1.36 × 10
Hz and 500 µs respectively. The GaN/NbN/SiC epi-HBAR is an electrically actuated, multi-mode phonon source that can be directly interfaced with NbN-based superconducting qubits or SiC-based spin qubits.
We report a systematic review and meta-analysis of research using animal models of chemotherapy-induced peripheral neuropathy (CIPN). We systematically searched 5 online databases in September 2012 ...and updated the search in November 2015 using machine learning and text mining to reduce the screening for inclusion workload and improve accuracy. For each comparison, we calculated a standardised mean difference (SMD) effect size, and then combined effects in a random-effects meta-analysis. We assessed the impact of study design factors and reporting of measures to reduce risks of bias. We present power analyses for the most frequently reported behavioural tests; 337 publications were included. Most studies (84%) used male animals only. The most frequently reported outcome measure was evoked limb withdrawal in response to mechanical monofilaments. There was modest reporting of measures to reduce risks of bias. The number of animals required to obtain 80% power with a significance level of 0.05 varied substantially across behavioural tests. In this comprehensive summary of the use of animal models of CIPN, we have identified areas in which the value of preclinical CIPN studies might be increased. Using both sexes of animals in the modelling of CIPN, ensuring that outcome measures align with those most relevant in the clinic, and the animal's pain contextualised ethology will likely improve external validity. Measures to reduce risk of bias should be employed to increase the internal validity of studies. Different outcome measures have different statistical power, and this can refine our approaches in the modelling of CIPN.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial ...cancers, which account for 80-90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1 × 10
engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
G-protein-coupled receptors (GPCRs) modulate many physiological processes by transducing a variety of extracellular cues into intracellular responses. Ligand binding to an extracellular orthosteric ...pocket propagates conformational change to the receptor cytosolic region to promote binding and activation of downstream signalling effectors such as G proteins and β-arrestins. It is well known that different agonists can share the same binding pocket but evoke unique receptor conformations leading to a wide range of downstream responses (‘efficacy’). Furthermore, increasing biophysical evidence, primarily using the β2-adrenergic receptor (β2AR) as a model system, supports the existence of multiple active and inactive conformational states. However, how agonists with varying efficacy modulate these receptor states to initiate cellular responses is not well understood. Here we report stabilization of two distinct β2AR conformations using single domain camelid antibodies (nanobodies)—a previously described positive allosteric nanobody (Nb80) and a newly identified negative allosteric nanobody (Nb60). We show that Nb60 stabilizes a previously unappreciated low-affinity receptor state which corresponds to one of two inactive receptor conformations as delineated by X-ray crystallography and NMR spectroscopy. We find that the agonist isoprenaline has a 15,000-fold higher affinity for β2AR in the presence of Nb80 compared to the affinity of isoprenaline for β2AR in the presence of Nb60, highlighting the full allosteric range of a GPCR. Assessing the binding of 17 ligands of varying efficacy to the β2AR in the absence and presence of Nb60 or Nb80 reveals large ligand-specific effects that can only be explained using an allosteric model which assumes equilibrium amongst at least three receptor states. Agonists generally exert efficacy by stabilizing the active Nb80-stabilized receptor state (R80). In contrast, for a number of partial agonists, both stabilization of R80 and destabilization of the inactive, Nb60-bound state (R60) contribute to their ability to modulate receptor activation. These data demonstrate that ligands can initiate a wide range of cellular responses by differentially stabilizing multiple receptor states.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Until the late 20th century, the idea of identifying wildfires in deep time was not generally accepted. One of the basic problems was the fact that charcoal-like wood fragments, so often found in ...sedimentary rocks and in coals, were termed fusain and, in addition, many researchers could not envision wildfires in peat-forming systems. The advent of Scanning Electron Microscopy and studies on modern charcoals and fossil fusains demonstrated beyond doubt that wildfire residues may be recognized in rocks dating back to at least 350 million years. Increasing numbers of studies on modern and fossil charcoal assemblages from the 1970s through the 1990s established the potential importance of wildfires in the fossil record, using Carboniferous examples in particular. Since the 1990s, extensive progress has been made in understanding modern wildfires and their byproducts. New techniques to study ancient charcoals have allowed considerable progress to be made to integrate modern and ancient fire studies, both before and after the evolution of mankind. Four important developments have made a reassessment of Carboniferous wildfires necessary: the recognition of the role of atmospheric oxygen in controlling the occurrence of wildfire; the development of new microscopical techniques allowing more detailed anatomical data to be obtained from charcoal; the integration of molecular studies with the evolution of fire traits; and new developments in or understanding of post-fire erosion/deposition systems.
Managing coral reefs for resilience to climate change is a popular concept but has been difficult to implement because the empirical scientific evidence has either not been evaluated or is sometimes ...unsupportive of theory, which leads to uncertainty when considering methods and identifying priority reefs. We asked experts and reviewed the scientific literature for guidance on the multiple physical and biological factors that affect the ability of coral reefs to resist and recover from climate disturbance. Eleven key factors to inform decisions based on scaling scientific evidence and the achievability of quantifying the factors were identified. Factors important to resistance and recovery, which are important components of resilience, were not strongly related, and should be assessed independently. The abundance of resistant (heat-tolerant) coral species and past temperature variability were perceived to provide the greatest resistance to climate change, while coral recruitment rates, and macroalgae abundance were most influential in the recovery process. Based on the 11 key factors, we tested an evidence-based framework for climate change resilience in an Indonesian marine protected area. The results suggest our evidence-weighted framework improved upon existing un-weighted methods in terms of characterizing resilience and distinguishing priority sites. The evaluation supports the concept that, despite high ecological complexity, relatively few strong variables can be important in influencing ecosystem dynamics. This is the first rigorous assessment of factors promoting coral reef resilience based on their perceived importance, empirical evidence, and feasibility of measurement. There were few differences between scientists' perceptions of factor importance and the scientific evidence found in journal publications but more before and after impact studies will be required to fully test the validity of all the factors. The methods here will increase the feasibility and defensibility of including key resilience metrics in evaluations of coral reefs, as well as reduce costs. Adaptation, marine protected areas, priority setting, resistance, recovery.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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