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"Leonard, Martin"
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The role of terrorism in twenty-first-century warfare
The role of terrorism in twenty-first-century warfare is a critical reflection on the major armed conflicts occurring during the 1990s and the first decade of the Twenty First Century. Conflicts in Bosnia, Kosovo, Chechnya, Iraq, Afghanistan, and Syria all involved the use of terrorism by one or more groups. Turning to the future, the book asks what does this mean for violent conflicts yet to come? Using a variety of case studies, Weinberg and Martin provide a systematic and comprehensive analysis of the role played by terrorism as a stand-alone tactic as well as one used to ignite broad-scale conflict, asking whether terrorist violence occurs during the early stages of an insurgency, as a leading indicator of a wider conflict, or if it is employed throughout the conflict's duration? The work also poses the question on what occasions does terrorism tend to occur as an armed conflict begins to subside, and when, in other words, is it a trailing indicator? This book is the product of Weinberg and Martin's thorough investigations into the role and timing of terrorist violence in multi-dimensional conflicts. It is an essential text for understanding the role that acts of terror play in contemporary warfare and future conflicts. -- Provided by publisher.
Book
Epistemic Markers in the Scientific Discourse
The central role of such epistemic concepts as theory , explanation , model , or mechanism is rarely questioned in philosophy of science. Yet, what is their actual use in the practice of science? Here, we deploy text-mining methods to investigate the usage of 61 epistemic notions in a corpus of full-text articles from the biological and biomedical sciences ( N = 73,771). The influence of disciplinary context is also examined by splitting the corpus into subdisciplinary clusters. The results reveal the intricate semantic networks that these concepts actually form in the scientific discourse, not always following our intuitions, at least in some parts of science.
Journal Article
Mononuclear phagocyte sub-types in vitro display diverse transcriptional responses to dust mite exposure
Mononuclear phagocytes (MNP), including macrophages and dendritic cells form an essential component of primary responses to environmental hazards and toxic exposures. This is particularly important in disease conditions such as asthma and allergic airway disease, where many different cell types are present. In this study, we differentiated CD34+ haematopoietic stem cells towards different populations of MNP in an effort to understand how different cell subtypes present in inflammatory disease microenvironments respond to the common allergen house dust mite (HDM). Using single cell mRNA sequencing, we demonstrate that macrophage subtypes MC
SPP1+
and MLC
MARCO+
display different patterns of gene expression after HDM challenge, noted especially for the chemokines CXCL5, CXCL8, CCL5 and CCL15. MLC
CD206Hi
alternatively activated macrophages displayed the greatest changes in expression, while neutrophil and monocyte populations did not respond. Further work investigated how pollutant diesel exhaust particles could modify these transcriptional responses and revealed that CXC but not CC type chemokines were further upregulated. Through the use of diesel particles with adsorbed material removed, we suggest that soluble pollutants on these particles are the active constituents responsible for the modifying effects on HDM. This study highlights that environmental exposures may influence tissue responses dependent on which MNP cell type is present, and that these should be considerations when modelling such events in vitro. Understanding the nuanced responsiveness of different immune cell types to allergen and pollutant exposure also contributes to a better understanding of how these exposures influence the development and exacerbation of human disease.
Journal Article
An overview of transcriptional regulation in response to toxicological insult
The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.
Journal Article
Induced pluripotent and CD34+ stem cell derived myeloid cells display differential responses to particle and dust mite exposure
Myeloid cells form an essential component of initial responses to environmental hazards and toxic exposures. The ability to model these responses in vitro is central to efforts tasked with identifying hazardous materials and understanding mechanisms of injury and disease. Induced pluripotent stem cell (iPSC) derived cells have been suggested as alternatives to more established primary cell testing systems for these purposes. iPSC derived macrophage and dendritic like cells were compared to CD34+ haematopoietic stem cell derived populations using transcriptomic analysis. Using single cell sequencing-based characterisation of iPSC derived myeloid cells, we identified transitional, mature and M2 like macrophages as well as dendritic like antigen presenting cells and fibrocytes. Direct transcriptomic comparisons between iPSC and CD34+ cell derived populations revealed higher expression of myeloid differentiation genes such as MNDA, CSF1R and CSF2RB in CD34+ cells, while iPSC populations had higher fibroblastic and proliferative markers. Exposure of differentiated macrophage populations to nanoparticle alone or in combination with dust mite, resulted in differential gene expression on combination only, with responses markedly absent in iPSC compared to CD34+ derived cells. The lack of responsiveness in iPSC derived cells may be attributable to lower levels of dust mite component receptors CD14, TLR4, CLEC7A and CD36. In summary, iPSC derived myeloid cells display typical characteristics of immune cells but may lack a fully mature phenotype to adequately respond to environmental exposures.
Journal Article
Modulatory effects of CeO2 nanoparticles on bleomycin-induced active pulmonary disease processes in animal and human airway epithelium models
Background
Understanding the impacts of inhaled insoluble nanomaterials as they are encountered in the environment and workplace, in injured lungs remains limited, particularly with respect to their role in the progression or mitigation of lung pathology. While some studies suggest potential protective effects of cerium(IV) oxide nanoparticles (CeO
2
NPs) under certain conditions, their influence during active disease processes is unclear. This study builds on prior work to investigate the effects of CeO
2
NP aerosols on bleomycin-induced pulmonary injury and active disease processes.
Method
To establish conditions of active pulmonary disease processes, bleomycin was used in both animal and airway epithelium models. Male Sprague-Dawley rats were intratracheally instilled with bleomycin or saline (control) followed by nose-only inhalation exposure to CeO
2
NP aerosols (diameter of ~ 43 nm) or control for 3 h per day for 4 days per week for one or two weeks. At three days postexposure, the animals were sacrificed for analysis of bronchoalveolar lavage (BAL) fluid, lung histopathology and global mRNA expression. Comparative in vitro studies were conducted to investigate biological responses at the cellular level, using 3D human small airway epithelium cultures (SmallAir™) exposed to CeO
2
NP aerosols (with a diameter of ~ 86 nm) at the air-liquid-interface at deposition doses comparable to those received in vivo in the small airway.
Results
In vivo, bleomycin treatment resulted in an increase in total BAL cells and fibrotic staining, and significant induction of inflammatory and oxidative stress, as shown by mRNA sequencing analysis. One week of exposure to CeO
2
NPs modified these responses by attenuating fibrotic staining and reducing the expression of genes associated with lung function, inflammation and epithelial-mesenchymal transition (EMT). In vitro, CeO
2
NP exposure modulated some bleomycin-induced cellular responses, although these models do not fully capture the complexity of whole body and tissue systems, highlighting limitations and considerations for future in vitro exposure studies.
Conclusions
In this study, inhaled CeO
2
NPs modulated lung injury responses in the context of active disease, with both potential protective effects and adverse outcomes. These findings demonstrate that the timing of CeO
2
NP exposure relative to disease progression is critical and highlight the need for hazard assessment frameworks to consider context-dependent effects, particularly in the presence of pre-existing lung injury.
Journal Article
The relationship between epigenetic age and the hallmarks of aging in human cells
Epigenetic clocks are mathematically derived age estimators that are based on combinations of methylation values that change with age at specific CpGs in the genome. These clocks are widely used to measure the age of tissues and cells 1,2 . The discrepancy between epigenetic age (EpiAge), as estimated by these clocks, and chronological age is referred to as EpiAge acceleration. Epidemiological studies have linked EpiAge acceleration to a wide variety of pathologies, health states, lifestyle, mental state and environmental factors 2 , indicating that epigenetic clocks tap into critical biological processes that are involved in aging. Despite the importance of this inference, the mechanisms underpinning these clocks remained largely uncharacterized and unelucidated. Here, using primary human cells, we set out to investigate whether epigenetic aging is the manifestation of one or more of the aging hallmarks previously identified 3 . We show that although epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.
Journal Article
Mechanistic insight into the impact of nanomaterials on asthma and allergic airway disease
Asthma is a chronic respiratory disease known for its high susceptibility to environmental exposure. Inadvertent inhalation of engineered or incidental nanomaterials is a concern for human health, particularly for those with underlying disease susceptibility. In this review we provide a comprehensive analysis of those studies focussed on safety assessment of different nanomaterials and their unique characteristics on asthma and allergic airway disease. These include
in vivo
and
in vitro
approaches as well as human and population studies. The weight of evidence presented supports a modifying role for nanomaterial exposure on established asthma as well as the development of the condition. Due to the variability in modelling approaches, nanomaterial characterisation and endpoints used for assessment in these studies, there is insufficient information for how one may assign relative hazard potential to individual nanoscale properties. New developments including the adoption of standardised models and focussed
in vitro
and
in silico
approaches have the potential to more reliably identify properties of concern through comparative analysis across robust and select testing systems. Importantly, key to refinement and choice of the most appropriate testing systems is a more complete understanding of how these materials may influence disease at the cellular and molecular level. Detailed mechanistic insight also brings with it opportunities to build important population and exposure susceptibilities into models. Ultimately, such approaches have the potential to more clearly extrapolate relevant toxicological information, which can be used to improve nanomaterial safety assessment for human disease susceptibility.
Journal Article
Affective Responses to Natural and Technological Disasters; An Evolutionary Perspective
Objectives and Method
Anecdotal reports indicate more severe psychological distress following technological catastrophes in comparison to natural disasters. Previous research also suggests a more negative evaluation of the outcomes of disasters if they are manmade. On the other hand, evolutionary neuroscience shows differential neural processing of ancient and modern threats. Building upon this literature, we probed valence and arousal ratings of stimuli depicting natural and technological disasters in several standardized affective stimuli datasets used in neuroscience and psychological research.
Results
Our results show that while technological disasters are rated as slightly less arousing than natural disasters they are rated as significantly more unpleasant.
Conclusion
It seems the evolutionary age of disasters is one of the factors that affect emotional experiences evoked by these threats and can impact our evaluations of catastrophes. We discuss how evolutionary psychology might explain our findings and help us to better understand the biological and learned roots of our biases in risk perception.
Journal Article