13,514 research outputs found
Epigenetics : a catalyst of plant immunity against pathogens
The plant immune system protects against pests and diseases. The recognition of stress-related molecular patterns triggers localised immune responses, which are often followed by longer-lasting systemic priming and/or up-regulation of defences. In some cases, this induced resistance (IR) can be transmitted to following generations. Such transgenerational IR is gradually reversed in the absence of stress at a rate that is proportional to the severity of disease experienced in previous generations. This review outlines the mechanisms by which epigenetic responses to pathogen infection shape the plant immune system across expanding time scales. We review the cis- and trans-acting mechanisms by which stress-inducible epigenetic changes at transposable elements (TEs) regulate genome-wide defence gene expression and draw particular attention to one regulatory model that is supported by recent evidence about the function of AGO1 and H2A.Z in transcriptional control of defence genes. Additionally, we explore how stress-induced mobilisation of epigenetically controlled TEs acts as a catalyst of Darwinian evolution by generating (epi)genetic diversity at environmentally responsive genes. This raises questions about the long-term evolutionary consequences of stress-induced diversification of the plant immune system in relation to the long-held dichotomy between Darwinian and Lamarckian evolution
Macrophage: A Key Player of Teleost Immune System
Fish, the free-living organisms, residing in aquatic environment, are earliest vertebrates with fully developed innate and adaptive immunity. Immune organs homologous to those of mammalian immune system are found in fish. Macrophages are best known for their role in immunity, basic function of which being cytokine production and phagocytosis. Due to environmental adaptation and whole genome duplication, macrophages in teleost are differently modulated (pro-inflammatory, M1-type, and anti-inflammatory/regulatory, M2-type) and perform a variety of different functions as compared with those of mammals. Phagocytosis is a major mechanism for removing pathogens and/or foreign particles in immune system and therefore is a critical component of the innate and adaptive immune system. One of the most competent phagocytes in teleost is found to be macrophages/monocytes. Increasing experimental evidence demonstrates that teleost phagocytic cells can recognize and destroy antigens to elicit adaptive immune responses that involve multiple cytokines. A detail understanding of teleost macrophages and phagocytosis would not only help in understanding the immune mechanism but will also help in disease prevention in teleost
Identification of Hindbrain Neural Substrates for Motor Initiation in the hatchling Xenopus laevis Tadpole
Animal survival profoundly depends on the ability to detect stimuli in the environment, process them and respond accordingly. In this respect, motor responses to a sensory stimulation evolved into a variety of coordinated movements, which involve the control of brain centres over spinal locomotor circuits. The hatchling Xenopus tadpole, even in its embryonic stage, is able to detect external sensory information and to swim away if the stimulus is considered noxious. To do so, the tadpole relies on well-known ascending sensory pathway, which carries the sensory information to the brain. When the stimulus is strong enough, descending interneurons are activated, leading to the excitation of spinal CPG neurons, which causes the undulatory movement of swimming. However, the activation of descending interneurons that marks the initiation of motor response appears after a long delay from the sensory stimulation. Furthermore, the long-latency response is variable in time, as observed in the slow-summating excitation measured in descending interneurons. These two features, i.e. long-latency and variability, cannot be explained by the firing time and pattern of the ascending sensory pathway of the Xenopus tadpole. Therefore, a novel neuronal population has been proposed to lie in the hindbrain of the tadpole, and being able to 'hold' the sensory information, thus accounting for the long and variable delay of swim initiation. In this work, the role of the hindbrain in the maintenance of the long and variable response to trunk skin stimulation is investigated in the Xenopustadpole at developmental stage 37/38. A multifaceted approach has been used to unravel the neuronal mechanisms underlying the delayed motor response, including behavioural experiments, electrophysiology analysis of fictive swimming, hindbrain extracellular recordings and imaging experiments. Two novel neuronal populations have been identified in the tadpole's hindbrain, which exhibit activation patterns compatible with the role of delaying the excitation of the spinal locomotor circuit. Future work on cellular properties and synaptic connections of these newly discovered populations might shed light on the mechanism of descending control active at embryonic stage. Identifying supraspinal neuronal populations in an embryonic organism could aid in understanding mechanisms of descending motor control in more complex vertebrates
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Role of Cerebrovascular Cells in Tau Processing Following Traumatic Brain Injury
Repetitive exposure to mild traumatic brain injuries (r-mTBI) sustained through the participation in contact sports can lead to chronic post-concussive symptoms and the development of neurodegenerative diseases such as Alzheimer’s disease and Chronic Traumatic Encephalopathy (CTE). A primary hallmark of CTE is the accumulation of pathogenic tau in neurons and astrocytes that surround small blood vessels in the brain. Chronic exposure to r-mTBI leads to elevated levels of extracellular tau and pathogenic tau accumulation in neurons, ultimately resulting in neuronal death. While the mechanisms responsible for pathogenic tau elimination from the brain are unclear, our prior work demonstrated that cells associated with the cerebrovasculature can interact with extracellular tau and may contribute to the removal of extracellular tau from the brain.
In this thesis, I examined the mechanisms through which the cerebrovascular cells eliminate extracellular tau from the brain and how those processes are impacted by r-mTBI. I demonstrated that brain vascular mural cells (pericytes and smooth muscle cells) progressively degenerate following exposure to r-mTBI consistent with what is observed in individuals with AD. This mural cell dysfunction impairs the ability of the cerebrovessels to interact with tau. Furthermore, I found that the cerebrovasculature can eliminate extracellular tau from the brain through caveolae-mediated endothelial transcytosis, which is impaired following chronic exposure to r-mTBI. The diminished tau transit across the blood-brain barrier following brain injury may be a contributing factor in the pathogenic tau accumulation observed in CTE.
A significant genetic risk factor for neurodegenerative diseases including AD and CTE is possession of the E4 isoform of Apolipoprotein E (ApoE). Astrocytes are the predominant source of ApoE in the brain, though there is very little understanding regarding their interactions with extracellular tau, particularly after exposure to head trauma. While the ApoE4 isoform has been associated with increased tau accumulation and cerebrovascular dysfunction after TBI, investigations into these associations are limited. The current studies found that while astrocytes internalize and release tau back into the extracellular space under normal conditions, these processes become dysfunctional following r-mTBI leading to astrocytic tau accumulation, which is further exacerbated by the ApoE4 isoform.
In summary, I identified the factors responsible for the elimination of extracellular tau across the BBB, which are impaired after head trauma. Therapeutic interventions that restore these processes may ameliorate the chronic accumulation of tau associated with neurodegenerative disease. These findings may be particularly important for individuals with the ApoE4 isoform, who are more susceptible to the pathophysiological sequelae of tau accumulation, particularly after exposure to r-mTBI
Gendered spaces in contemporary Irish poetry
The thrust of this thesis is summarized by the following questions: How does contemporary Irish poetry migrate from traditional conceptions of identity drawn on by the cultural nationalism of the Irish Literary Revival, and what effects does this have on understanding gendered and national identity formation? Chapters are on the following: Seamus Heaney, Tom Paulin, Paul Muldoon, MedbhMcGuckian, Eavan Boland and Sara Berkeley. These poets are chosen for discussion since their work most effectively engages with the relationship between woman and nation, the representation of gendered national identity, and the importance of feminist and post-colonial theorization. Focusing on poetry worth and South of the border from the last fifteen years, the thesis asks how a younger generation of poets provide a response to nationality which is significantly different from their predecessors. The thesis is composed of three parts: the first understand how the male poets depart from conventional conceptions of the nation with reference to post-colonial theorization; the second explores how feminist theorization informs readings of how the female poets respond to the nation; the final part investigates migration in the poetry and problematizes this in terms of post-nationalism. Discussing the issue of deterritorialization in Irish poetry, the thesis notice how as the poets attempt to take flight from the mythologies of nationhood, they undermine the monoliths of gendered and national identity inscribed within Irish political discourse, which is typified at a representative level by the figure of Mother Ireland or Cathleen Ni Houlihan. Investigating the ways in which gender and nation, and the body and space are reinscribed by the poets, the thesis argues that their poetry challenges authentic conceptions of Irish identity and the nation-state, so as to loosen the legacy of a colonial and nationalist inheritance
Simulating the X-ray emission of hot gas in groups and clusters
As some of the largest gravitationally bound objects in the Universe, galaxy groups
and clusters provide a unique laboratory for testing models of cosmology and galaxy
evolution. While many of the basic properties of halos are determined by the
dissipationless dark matter component, the baryonic components that govern the
appearance of the visible matter such as the galaxies and the virialised hot gas, are
less well understood. As such the co-evolution of galaxies, gas, and black holes within
groups and clusters can help us examine galaxy evolution. By leveraging the benefits
of simulations we can closely investigate this evolution and the effects of feedback.
SIMBA is a cosmological hydrodynamical simulation run using the GIZMO code, that
utilises a novel approach to black hole growth and feedback. Deviations of the X-ray scaling relations within SIMBA from self-similarity give us insight into how the
implemented feedback affects halo evolution. It is then possible to determine more
specifically where feedback is altering halos through their X-ray profiles. Through
this work into the global X-ray properties of halos within SIMBA I have established
a baseline from which to start investigating the evolution of individual halos. Tracing
halos back through time allows us to pinpoint the moments, and events, which lead to
significant changes both in global X-ray properties, and the finer details of the X-ray
profiles. While the initial work was done using X-rays generated through PYGAD,
further work was achieved through the combination of pyXSIM, SOXS telescope
simulator, and XSPEC, to generate mock observations and allow for the more direct
comparison of simulations to observations. This ability to accurately create mock
observations from past telescopes such as Chandra aptly leads to the application of
these tools towards simulating observations for future X-ray telescope projects such as
Athena. As such we move from using these tools to validate the simulation, to using
the simulations to make predictions
Evolutionary ecology of biological rhythms in malaria parasites
Biological rhythms are a ubiquitous feature of life and are assumed to allow organisms coordinate their
activities with daily rhythms in the abiotic environment resulting from the rotation of the Earth every 24
hours. The genes and molecular mechanisms underpinning circadian clocks in multicellular organisms
are relatively well understood in contrast to the evolution and ecology of circadian rhythms. Circadian
rhythms mediate interactions between organisms; from predators and prey, to mating behaviours
between males and females, to hosts and parasites. The role of daily rhythms in infections is gaining
traction because explaining the regulatory mechanisms and fitness consequences of biological rhythms
exhibited by parasites and hosts offers new avenues to treat infections. Here, I explore how periodicity
in parasite traits is generated and why daily rhythms matter for parasite fitness. My work focuses on
malaria (Plasmodium) parasites which exhibit developmental rhythms during replication in the
mammalian host’s blood and during transmission to insect vectors. Rhythmic in-host parasite replication
is responsible for eliciting inflammatory responses, severe anaemia, fuels transmission, and can confer
tolerance to anti-parasite drugs. Thus, understanding both how and why the timing and synchrony of
parasites are connected to the daily rhythms of hosts and vectors may make treatment more effective
and less toxic to hosts.
My papers integrate an evolutionary ecology approach with chronobiology and parasitology to
investigate how host-parasite-vector interactions shape the evolution of rhythmicity in parasites traits. I
have used a rodent malaria parasite model system (Plasmodium chabaudi) for my experiments,
capitalising on the tractability of this model for the human malaria, P. falciparum. P. chabaudi exhibits a
24-hour rhythm in replication, facilitates ecologically realistic studies because experiments can be
carried out in vivo (compared to the in vitro limitations on studying human parasites), and perturbations
to the timing of the in-host and in-vector environments are straightforward. My findings include:
1) Perturbing the timing of parasite rhythms with respect to the timing of host rhythms (analogous
to giving the parasites “jet lag”), results in a fitness cost to the parasites, evident by a 50%
reduction in both asexually replicating and transmission stage parasites.
2) The consequences of temporal mismatch to the host manifest very early in the infection (within
48 hours, i.e. the first 1-2 cycles of replication) and are dependent on the parasite stage by
which infections are initiated (0-12 hour old parasites suffer a cost, whereas 12-24 hour
parasites benefit).
3) The timing of the parasite replication cycle is independent of the canonical ‘core’ host clock (i.e.
transcription translation feedback loop) and instead depends on the timing of feeding-fasting
rhythms of the host.
4) If perturbed, the timing of the parasite’s rhythm reschedules to regain synchrony with the
timing of the host’s rhythm within 7 replication cycles. Specifically, parasites achieve this by
speeding up the replication rhythm by 2-3 hours per cycle, and the rate of rescheduling is
independent of parasite density.
5) Naturally asynchronous Plasmodium species are ‘resistant’ to conditions that lead to alignment
with host rhythms in synchronously replicating species. This suggests that unknown ecological
differences between these parasite species selects for vastly different schedules of within-host
replication rather than some species being constrained to replicate asynchronously.
6) In addition to the timing of parasite rhythms impacting directly upon within-host dynamics,
timing also matters – albeit indirectly - for transmission, via impacts on the population dynamics
of the vector. For example, receiving a blood meal in the morning makes mosquitoes more likely
to lay eggs, lay slightly sooner and have a larger clutch size than those feeding at night. Yet,
whilst mosquitoes infected with malaria die sooner, the effects of taking a blood meal at
different times of day do not impact transmission of an asynchronously replicating malaria
parasite.
It is beneficial for parasites to be in synchronization with their host’s feeding-fasting rhythms and
plasticity in the IDC duration facilitates this synchrony by enabling parasites to make small daily changes
to their IDC schedule when necessary. Understanding the extent of, and limits on, plasticity in the IDC
schedule is important as it may reveal targets for novel interventions, such as drugs to disrupt IDC
regulation and preventing IDC dormancy conferring tolerance to existing drugs. More generally, our
results provide a demonstration of the adaptive value of biological rhythms and the utility of using an
evolutionary framework to understand parasite traits
Maternal immunometabolism adaptation in pregnancy
Pregnant women undergo a series of metabolic and immunologic changes to ensure provision of nutrients to, and prevent rejection of, the fetus. To ensure continuous supply of glucose to the fetus, the mother increases glucose production, glucose intolerance and insulin resistance. To meet her own energy demands, the mother transitions from lipid storage to lipolysis. To prevent rejection of the fetal semi-allograft, the mother’s immune system must be regulated, whilst maintaining protection against pathogens. Hypothesis: Well-recognised metabolic changes in pregnancy could impact maternal immune function. The aims of this project are to landscape the lipidomic profile using novel mass spectrometry techniques, and to determine whether monocytes undergo metabolic adaptation, if this occurs at 28 weeks of gestation, and if maternal obesity sabotages immunological adaptations. In addition, aims included investigation into the mechanisms which may protect the mother and fetus against SARS-CoV-2. Key findings unveiled significant phenotypic adaptations in the monocyte subsets during pregnancy, which are sabotaged by obesity. As the effect of maternal obesity is poorly understood, other immunological adaptations were investigated which revealed a shift to a Th1 and Th17 response which might contribute to the detrimental effects of obesity on pregnancy. At term, the monocytes illustrate a strong metabolic adaptation where their oxidative phosphorylation capabilities are reduced, confirmed by alterations in their mitochondria, with a downstream effect on their functionality with reduced production of lipid mediators and cytokines. While risk of infection with SARS-CoV-2 is low to pregnant women and the fetus, there is increased risk of preterm birth and admission into ICU. The fetus is relatively protected against infection, with cases of vertical transmission being rare. This thesis illustrates an elevated presence of soluble SARS-CoV-2 related molecules in breast milk and amniotic fluid which are postulated to act as decoy traps for the virus, which protects the neonate. In conclusion, this thesis has revealed novel findings into the immunometabolism adaptation to pregnancy
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