A systematic methodology to assess the identity of plants in historical texts: A case study based on the Byzantine pharmacy text John the Physician's Therapeutics.

ETHNOPHARMACOLOGICAL RELEVANCE: In recent decades, the study of historical texts has attracted research interest, particularly in ethnopharmacology. All studies of the materia medica cited in ancient and medieval texts share a concern, however, as to the reliability of modern identifications of these substances. Previous studies of European or Mediterranean texts relied mostly on authoritative dictionaries or glossaries providing botanical identities for the historical plant names in question. Several identities they suggest, however, are questionable and real possibility of error exists. AIM OF THE STUDY: This study aims to develop and document a novel and interdisciplinary methodology providing more objective assessment of the identity of the plants (and minerals) described in these resources. MATERIALS AND METHODS: We developed an iterative experimental approach, using the 13th century Byzantine recipe text John the Physician's Therapeutics in its Commentary version (JC) as a case study. The methodology has six stages and relies on comparative analyses including statistical evaluation of botanical descriptions and information about medicinal uses drawn from both historical and modern sources. Stages 1-4 create the dataset, stage 5 derives the primary outcomes to be reviewed by experts in stage 6. RESULTS: Using Disocorides' De Materia Medica (DMM) (1st century CE) as the culturally related reference text for the botanical descriptions of the plants cited in JC, allowed us to link the 194 plants used medicinally in JC with 252 plants cited in DMM. Our test sample for subsequent analyses consisted of the 50 JC plant names (corresponding to 61 DMM plants) for which DMM holds rich morphological information, and the 130 candidate species which have been suggested in the literature as potential botanical identities of those 50 JC plant names. Statistical evaluation of the comparative analyses revealed that in the majority of the cases, our method detected the candidate species having a higher likelihood of being the correct attribution from among the pool of suggested candidates. Final assessment and revision provided a list of the challenges associated with applying our methodology more widely and recommendations on how to address these issues. CONCLUSIONS: We offer this multidisciplinary approach to more evidence-based assessment of the identity of plants in historical texts providing a measure of confidence for each suggested identity. Despite the experimental nature of our methodology and its limitations, its application allowed us to draw conclusions about the validity of suggested candidate plants as well as to distinguish between alternative candidates of the same historical plant name. Fully documenting the methodology facilitates its application to historical texts of any kind of cultural or linguistic background.

Pharmaceutical Terminology in Ancient and Medieval Time - andrachne, chrysocolla and Others.

Ancient and medieval pharmacological and medical texts contain a substantial amount of plant and mineral names. In some cases, the identification is straightforward. But for the majority of the data, we are unable to identify these ingredients with high certainty. In this paper, we discuss a selection of plant and mineral names both from a humanities and sciences point of view. In one case, the scientists were even able to examine a plant in situ. The conclusion of our paper is that a close collaboration between sciences and humanities is essential to avoid mistakes in the identification of materia medica.

Ectopic activation of the miR-200c-EpCAM axis enhances antitumor T cell responses in models of adoptive cell therapy.

Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF). miR-200c elicited these changes by suppressing the transcription factor Zeb1 and thereby inducing genes characteristic of epithelial cells. Overexpression of one of these genes, Epcam, was sufficient to augment therapeutic T cell responses against both solid and liquid tumors. These results identify the miR-200c­EpCAM axis as an avenue for improving ACT and demonstrate that select genetic perturbations can produce phenotypically distinct T cells with advantageous therapeutic properties.

TOX is a critical regulator of tumour-specific T cell differentiation.

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.

Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody.

Depletion of T regulatory cells (Tregs) in the tumor microenvironment is a promising cancer immunotherapy strategy. Current approaches for depleting Tregs are limited by lack of specificity and concurrent depletion of anti-tumor effector T cells. The transcription factor forkhead box p3 (Foxp3) plays a central role in the development and function of Tregs and is an ideal target in Tregs, but Foxp3 is an intracellular, undruggable protein to date. We have generated a T cell receptor mimic antibody, "Foxp3-#32," recognizing a Foxp3-derived epitope in the context of HLA-A*02:01. The mAb Foxp3-#32 selectively recognizes CD4 + CD25 + CD127low and Foxp3 + Tregs also expressing HLA-A*02:01 and depletes these cells via antibody-mediated cellular cytotoxicity. Foxp3-#32 mAb depleted Tregs in xenografts of PBMCs from a healthy donor and ascites fluid from a cancer patient. A TCRm mAb targeting intracellular Foxp3 epitope represents an approach to deplete Tregs.

A Tournaisian (earliest Carboniferous) conglomerate-preserved non-marine faunal assemblage and its environmental and sedimentological context.

A conglomerate bed from the Tournaisian Ballagan Formation of Scotland preserves a rich array of vertebrate and other nonmarine fossils providing an insight into the wider ecosystem and paleoenvironment that existed during this pivotal stage of Earth history. It challenges hypotheses of a long-lasting post-extinction trough following the end-Devonian extinction event. The fauna recovered includes a wide size range of tetrapods, rhizodonts, and dipnoans, from tiny juveniles or small-bodied taxa up to large adults, and more than one taxon of each group is likely. Some fauna, such as actinopterygians and chondrichthyans, are rare as macrofauna but are better represented in the microfossil assemblage. The fauna provides evidence of the largest Carboniferous lungfish ever found. The specimens are preserved in a localized, poorly-sorted conglomerate which was deposited in the deepest part of a river channel, the youngest of a group of channels. In addition to the fossils (micro- and macro-), the conglomerate includes locally-derived clasts of paleosols and other distinctive elements of the surrounding floodplains. Charcoal fragments represent small woody axes and possible larger trunk tissue from arborescent pteridosperms. Preservation of the fossils indicates some aerial exposure prior to transport, with abrasion from rolling. The findings presented here contrast with other published trends in vertebrate size that are used to interpret a reduction in maximum sizes during the Tournaisian. The richness of the fauna runs counter to the assumption of a depauperate nonmarine fauna following the end-Devonian Hangenberg event, and charcoal content highlights the occurrence of fire, with the requisite levels of atmospheric oxygen during that stage.

Chromatin states define tumour-specific T cell dysfunction and reprogramming.

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 PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi 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.

Global combustion: the connection between fossil fuel and biomass burning emissions (1997-2010).

Humans use combustion for heating and cooking, managing lands, and, more recently, for fuelling the industrial economy. As a shift to fossil-fuel-based energy occurs, we expect that anthropogenic biomass burning in open landscapes will decline as it becomes less fundamental to energy acquisition and livelihoods. Using global data on both fossil fuel and biomass burning emissions, we tested this relationship over a 14 year period (1997-2010). The global average annual carbon emissions from biomass burning during this time were 2.2 Pg C per year (±0.3 s.d.), approximately one-third of fossil fuel emissions over the same period (7.3 Pg C, ±0.8 s.d.). There was a significant inverse relationship between average annual fossil fuel and biomass burning emissions. Fossil fuel emissions explained 8% of the variation in biomass burning emissions at a global scale, but this varied substantially by land cover. For example, fossil fuel burning explained 31% of the variation in biomass burning in woody savannas, but was a non-significant predictor for evergreen needleleaf forests. In the land covers most dominated by human use, croplands and urban areas, fossil fuel emissions were more than 30- and 500-fold greater than biomass burning emissions. This relationship suggests that combustion practices may be shifting from open landscape burning to contained combustion for industrial purposes, and highlights the need to take into account how humans appropriate combustion in global modelling of contemporary fire. Industrialized combustion is not only an important driver of atmospheric change, but also an important driver of landscape change through companion declines in human-started fires.This article is part of the themed issue 'The interaction of fire and mankind'.

Living on a flammable planet: interdisciplinary, cross-scalar and varied cultural lessons, prospects and challenges.

Living with fire is a challenge for human communities because they are influenced by socio-economic, political, ecological and climatic processes at various spatial and temporal scales. Over the course of 2 days, the authors discussed how communities could live with fire challenges at local, national and transnational scales. Exploiting our diverse, international and interdisciplinary expertise, we outline generalizable properties of fire-adaptive communities in varied settings where cultural knowledge of fire is rich and diverse. At the national scale, we discussed policy and management challenges for countries that have diminishing fire knowledge, but for whom global climate change will bring new fire problems. Finally, we assessed major fire challenges that transcend national political boundaries, including the health burden of smoke plumes and the climate consequences of wildfires. It is clear that to best address the broad range of fire problems, a holistic wildfire scholarship must develop common agreement in working terms and build across disciplines. We must also communicate our understanding of fire and its importance to the media, politicians and the general public.This article is part of the themed issue 'The interaction of fire and mankind'.

The interaction of fire and mankind: Introduction.

Fire has been an important part of the Earth system for over 350 Myr. Humans evolved in this fiery world and are the only animals to have used and controlled fire. The interaction of mankind with fire is a complex one, with both positive and negative aspects. Humans have long used fire for heating, cooking, landscape management and agriculture, as well as for pyrotechnologies and in industrial processes over more recent centuries. Many landscapes need fire but population expansion into wildland areas creates a tension between different interest groups. Extinguishing wildfires may not always be the correct solution. A combination of factors, including the problem of invasive plants, landscape change, climate change, population growth, human health, economic, social and cultural attitudes that may be transnational make a re-evaluation of fire and mankind necessary. The Royal Society meeting on Fire and mankind was held to address these issues and the results of these deliberations are published in this volume.This article is part of the themed issue 'The interaction of fire and mankind'.

Fire history on the California Channel Islands spanning human arrival in the Americas.

Recent studies have suggested that the first arrival of humans in the Americas during the end of the last Ice Age is associated with marked anthropogenic influences on landscape; in particular, with the use of fire which, would have given even small populations the ability to have broad impacts on the landscape. Understanding the impact of these early people is complicated by the dramatic changes in climate occurring with the shift from glacial to interglacial conditions. Despite these difficulties, we here attempt to test the extent of anthropogenic influence using the California Channel Islands as a smaller, landscape-scale test bed. These islands are famous for the discovery of the 'Arlington Springs Man', which are some of the earliest human remains in the Americas. A unifying sedimentary charcoal record is presented from Arlington Canyon, Santa Rosa Island, based on over 20 detailed sedimentary sections from eight key localities. Radiocarbon dating was based on thin, fragile, long fragments of charcoal in order to avoid the 'inbuilt' age problem. Radiocarbon dating of 49 such fragments has allowed inferences regarding the fire and landscape history of the Canyon ca 19-11 ka BP. A significant period of charcoal deposition is identified approximately 14-12.5 ka BP and bears remarkable closeness to an estimated age range of the first human arrival on the islands.This article is part of the themed issue 'The interaction of fire and mankind'.

The impact of fire on the Late Paleozoic Earth system.

Analyses of bulk petrographic data indicate that during the Late Paleozoic wildfires were more prevalent than at present. We propose that the development of fire systems through this interval was controlled predominantly by the elevated atmospheric oxygen concentration (p(O2)) that mass balance models predict prevailed. At higher levels of p(O2), increased fire activity would have rendered vegetation with high-moisture contents more susceptible to ignition and would have facilitated continued combustion. We argue that coal petrographic data indicate that p(O2) rather than global temperatures or climate, resulted in the increased levels of wildfire activity observed during the Late Paleozoic and can, therefore, be used to predict it. These findings are based upon analyses of charcoal volumes in multiple coals distributed across the globe and deposited during this time period, and that were then compared with similarly diverse modern peats and Cenozoic lignites and coals. Herein, we examine the environmental and ecological factors that would have impacted fire activity and we conclude that of these factors p(O2) played the largest role in promoting fires in Late Paleozoic peat-forming environments and, by inference, ecosystems generally, when compared with their prevalence in the modern world.

Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells.

Low linear energy transfer (LET) ionizing radiation (IR) is an important form of therapy for acute leukemias administered externally or as radioimmunotherapy. IR is also a potential source of DNA damage. High LET IR produces structurally different forms of DNA damage and has emerged as potential treatment of metastatic and hematopoietic malignancies. Therefore, understanding mechanisms of resistance is valuable. We created stable myeloid leukemia HL60 cell clones radioresistant to either γ-rays or α-particles to understand possible mechanisms in radioresistance. Cross-resistance to each type of IR was observed, but resistance to clustered, complex α-particle damage was substantially lower than to equivalent doses of γ-rays. The resistant phenotype was driven by changes in: apoptosis; late G2/M checkpoint accumulation that was indicative of increased genomic instability; stronger dependence on homology-directed repair; and more robust repair of DNA double-strand breaks and sublethal-type damage induced by γ-rays, but not by α-particles. The more potent cytotoxicity of α-particles warrants their continued investigation as therapies for leukemia and other cancers.

The human dimension of fire regimes on Earth.

Humans and their ancestors are unique in being a fire-making species, but 'natural' (i.e. independent of humans) fires have an ancient, geological history on Earth. Natural fires have influenced biological evolution and global biogeochemical cycles, making fire integral to the functioning of some biomes. Globally, debate rages about the impact on ecosystems of prehistoric human-set fires, with views ranging from catastrophic to negligible. Understanding of the diversity of human fire regimes on Earth in the past, present and future remains rudimentary. It remains uncertain how humans have caused a departure from 'natural' background levels that vary with climate change. Available evidence shows that modern humans can increase or decrease background levels of natural fire activity by clearing forests, promoting grazing, dispersing plants, altering ignition patterns and actively suppressing fires, thereby causing substantial ecosystem changes and loss of biodiversity. Some of these contemporary fire regimes cause substantial economic disruptions owing to the destruction of infrastructure, degradation of ecosystem services, loss of life, and smoke-related health effects. These episodic disasters help frame negative public attitudes towards landscape fires, despite the need for burning to sustain some ecosystems. Greenhouse gas-induced warming and changes in the hydrological cycle may increase the occurrence of large, severe fires, with potentially significant feedbacks to the Earth system. Improved understanding of human fire regimes demands: (1) better data on past and current human influences on fire regimes to enable global comparative analyses, (2) a greater understanding of different cultural traditions of landscape burning and their positive and negative social, economic and ecological effects, and (3) more realistic representations of anthropogenic fire in global vegetation and climate change models. We provide an historical framework to promote understanding of the development and diversification of fire regimes, covering the pre-human period, human domestication of fire, and the subsequent transition from subsistence agriculture to industrial economies. All of these phases still occur on Earth, providing opportunities for comparative research.

Fire and the spread of flowering plants in the Cretaceous.

We suggest that the spread of angiosperms in the Cretaceous was facilitated by novel fire regimes. Angiosperms were capable of high productivity and therefore accumulated flammable biomass ('fuel') more rapidly than their predecessors. They were capable of rapid reproduction, allowing populations to spread despite frequent disturbance. We evaluate the evidence for physical conditions conducive to fires in the Cretaceous. These included high temperatures, seasonally dry climate and higher atmospheric oxygen than current levels. We evaluate novel properties of angiosperms that contributed to rapid biomass accumulation, and to their ability to thrive in frequently disturbed environments. We also review direct evidence for Cretaceous fires. Charcoal mesofossils are common in Cretaceous deposits of the Northern Hemisphere. Inertinite, the charcoal component of coal, is common throughout the Cretaceous and into the Palaeocene, but declined steeply from the Eocene when angiosperm-dominated forests became widespread. Direct and indirect evidence is consistent with angiosperms initiating novel fire regimes, promoting angiosperm spread in the Cretaceous. Several traits are consistent with frequent surface fires. We suggest that forest was slow to develop until the Eocene, when fire activity dropped to very low levels. The causes and consequences of fires in the deep past warrant greater attention.

No evidence of nanodiamonds in Younger-Dryas sediments to support an impact event.

The causes of the late Pleistocene megafaunal extinctions in North America, disappearance of Clovis paleoindian lithic technology, and abrupt Younger-Dryas (YD) climate reversal of the last deglacial warming in the Northern Hemisphere remain an enigma. A controversial hypothesis proposes that one or more cometary airbursts/impacts barraged North America ≈12,900 cal yr B.P. and caused these events. Most evidence supporting this hypothesis has been discredited except for reports of nanodiamonds (including the rare hexagonal polytype) in Bølling-Ållerod-YD-boundary sediments. The hexagonal polytype of diamond, lonsdaleite, is of particular interest because it is often associated with shock pressures related to impacts where it has been found to occur naturally. Unfortunately, previous reports of YD-boundary nanodiamonds have left many unanswered questions regarding the nature and occurrence of the nanodiamonds. Therefore, we examined carbon-rich materials isolated from sediments dated 15,818 cal yr B.P. to present (including the Bølling-Allerod-YD boundary). No nanodiamonds were found in our study. Instead, graphene- and graphene/graphane-oxide aggregates are ubiquitous in all specimens examined. We demonstrate that previous studies misidentified graphene/graphane-oxide aggregates as hexagonal diamond and likely misidentified graphene as cubic diamond. Our results cast doubt upon one of the last widely discussed pieces of evidence supporting the YD impact hypothesis.