226 research outputs found
Cell states along oligodendrocyte development and disease
The brain, one of the most complex organs in the body, where an immense diversity of cell
states emerges from simple structure, where function arises from sets of regulatory principles
and pattern persist where individual cells do not. Revealing the regulatory underpinnings of
the brain, from unspecified cell states to diversity, is paramount for achieving a thorough
understanding of the development process and generating insight into the disease states of the
brain. This thesis is an exploration into how canonical regulatory factors and elements, such
as transcription factors and genes, lock a regulatory system in a multi-outcome network with
limited possible states.
The work in this thesis focuses on the oligodendrocyte lineage, a glial cell known for itâs
supportive role in the central nervous system, where it facilitates electrical transmission
through the enscheathment of axons. Oligodendrocytes (OLs) lie at the heart of multiple
sclerosis (MS), a disease where an immune response is mounted against myelin. As a
response, oligodendrocyte precursor cells (OPCs) move towards lesions and remyelinate
axons, however, this mechanism fails in later stages of the disease. Thus, an understanding to
how OPCs develop is vital to amelioration of the altered oligodendrocyte population.
In Paper I we reveal a previously underestimated heterogeneity within the oligodendrocyte
lineage in mouse. We show that OL maturation is an ongoing process, albeit, decreasing in
frequency with age. Furthermore, complex wheel training in mice revealed that the OLs
respond to this challenge through an increase in differentiation.
Paper II investigates the cellular response in the experimental autoimmune encephalomyelitis
(EAE) disease mouse model of MS, where we find a tailored response by the
resident OL population, changed from its normal transcriptional program, expressing a
spectrum of genes related to survival, immunological stimulation, phagocytosis, and active
differentiation. Furthermore, we provide evidence that OLs can elicit responses from T cells.
In Paper III we explore the different waves of OPC generation in the developing mouse
brain at embryonic day 13.5 and postnatal day 7. We show that recently Pdgfra expressing
cells at the E13.5 time point exhibit a multitude of patterning genes, and we show the
emergence of a possible OPC progenitor through the inclusion of a bridging E17.5 time point
population. This pre-OPC population is biased towards expressing glial and OL lineage
specifying genes such as Olig1, Olig2, Ptprz1, and Bcan. Furthermore, lineage tracing of
OPC developmental waves, shows no transcriptional differences, leading us to conclude that
OPCs are generally naĂŻve to the time or region of specification.
In Paper IV we show that we are able to detect OPC formation in the developing human
forebrain. We detect OPCs at the earliest sampled time point post conception week 8. We
attempt to recover the path of OPC formation, and investigate the regulatory dynamics in the
specification of OPCs
Altered human oligodendrocyte heterogeneity in multiple sclerosis
Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the sameâthose from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex2, and single-cell analysis of the mouse central nervous system identified further differences3,4. However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches
Mapping In Vivo Tumor Oxygenation within Viable Tumor by 19F-MRI and Multispectral Analysis
AbstractQuantifying oxygenation in viable tumor remains a major obstacle toward a better understanding of the tumor microenvironment and improving treatment strategies. Current techniques are often complicated by tumor heterogeneity. Herein, a novel in vivo approach that combines 19F magnetic resonance imaging (19F-MRI)R1 mapping with diffusionbased multispectral (MS) analysis is introduced. This approach restricts the partial pressure of oxygen (pO2) measurements to viable tumor, the tissue of therapeutic interest. The technique exhibited sufficient sensitivity to detect a breathing gas challenge in a xenograft tumor model, and the hypoxic region measured by MS 19F-MRI was strongly correlated with histologic estimates of hypoxia. This approach was then applied to address the effects of antivascular agents on tumor oxygenation, which is a research question that is still under debate. The technique was used to monitor longitudinal pO2 changes in response to an antibody to vascular endothelial growth factor (B20.4.1.1) and a selective dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor (GDC-0980). GDC-0980 reduced viable tumor pO2 during a 3-day treatment period, and a significant reduction was also produced by B20.4.1.1. Overall, this method provides an unprecedented view of viable tumor pO2 and contributes to a greater understanding of the effects of antivascular therapies on the tumor's microenvironment
Pest categorisation of Scirtothrips citri
The Panel on Plant Health performed a pest categorisation of the citrus thrips,
Scirtothrips citri
(Moulton) (Thysanoptera: Thripidae), for the European Union (EU). This is a well-de
fi
ned and
distinguishable species, occurring in North America and Asia. Its precise distribution in Asia is
uncertain.
S. citri
is a pest of citrus and blueberries and has been cited on over 50 different host
species in 33 plant families. Whether all plants reported as hosts are true hosts, allowing population
development of
S. citri
, is uncertain.
S. citri
feeds exclusively on young actively growing foliage and
fruit. It is not known to occur in the EU and is listed in Annex IIAI of 2000/29/EC as a harmful
organism. The international trade of hosts, as either plants for planting or cut
fl
owers, provide
potential pathways into the EU. However, current EU legislation prohibits the import of citrus plants for
planting. Furthermore, measures aimed at the import of plants for planting in a dormant stage (no
young foliage or fruits present) with no soil/growing medium attached, decreases the likelihood of the
pest
â
s entry via other hosts. Considering that there are regional climatic similarities where
S. citri
occurs in the USA with climates in the EU, and taking EU host distribution into account,
S. citri
has the
potential to establish in the EU, especially in citrus and blueberry growing regions around the
Mediterranean where quality losses in citrus and yield losses in blueberry could occur. Phytosanitary
measures are available to inhibit the likelihood of introduction of
S. citri
from infested countries.
Considering the criteria within the remit of EFSA to assess its status as a potential Union quarantine
pest (QP) or as a potential regulated non-quarantine pest (RNQP),
S. citri
meets with no uncertainties
the criteria assessed by EFSA for consideration as a potential Union QP
Pest categorisation of Toxoptera citricida
23The European Commission requested EFSA to conduct a pest categorisation of Toxoptera citricida (Hemiptera: Aphididae), an oligophagous aphid developing and reproducing parthenogenetically on tender leaf and flower flush of citrus (Rutaceae). T.citricida is a taxonomic entity with reliable methods available for detection and identification. It is regulated in the EU by Council Directive 2000/29/EC where it is listed in Annex IIAI as a harmful organism whose introduction and spread into the EU shall be banned. T.citricida is native to tropical regions of Southeast Asia and has spread to most citrus-growing areas worldwide, except California and the Mediterranean basin, causing significant damage to citrus as it is the most efficient vector of the Citrus tristeza virus (CTV). T.citricida occurs in Madeira and, with a restricted distribution, in the north-west of the Iberian Peninsula, mostly on backyard citrus trees. This may have hindered the effectiveness of the official control measures in these areas. There are further phytosanitary measures in place in the EU in order to limit entry via traded commodities. Citrus plants for planting are regulated and are a closed pathway. However, there is uncertainty regarding host status of some non-rutaceous plants on which this aphid has been recorded and so other plant genera may provide additional pathways. The EFSA Plant Health Panelconcludes that the establishment of T.citricida in the main EU citrus growing areas around the Mediterranean would have significant impacts because of its ability to vector CTV. Considering the criteria within the remit of EFSA to assess the status as a potential Union quarantine pest (QP), as a potential protected zone quarantine pest (PZQP) or as a potential regulated non-quarantine pest (RNQP), T.citricida meets with no uncertainties the criteria assessed by EFSA for consideration as a potential Union QP.openopenJeger, Michael; Bragard, Claude; Caffier, David; Candresse, Thierry; Chatzivassiliou, Elisavet; DehnenâSchmutz, Katharina; Gilioli, Gianni; GrĂ©goire, JeanâClaude; Jaques Miret, Josep Anton; Navarro, Maria Navajas; Niere, Björn; Parnell, Stephen; Potting, Roel; Rafoss, Trond; Rossi, Vittorio; Urek, Gregor; Van Bruggen, Ariena; Van der Werf, Wopke; West, Jonathan; Winter, Stephan; Gardi, Ciro; Bergeretti, Filippo; MacLeod, AlanJeger, Michael; Bragard, Claude; Caffier, David; Candresse, Thierry; Chatzivassiliou, Elisavet; Dehnenâschmutz, Katharina; Gilioli, Gianni; GrĂ©goire, Jeanâclaude; Jaques Miret, Josep Anton; Navarro, Maria Navajas; Niere, Björn; Parnell, Stephen; Potting, Roel; Rafoss, Trond; Rossi, Vittorio; Urek, Gregor; Van Bruggen, Ariena; Van der Werf, Wopke; West, Jonathan; Winter, Stephan; Gardi, Ciro; Bergeretti, Filippo; Macleod, Ala
Pest categorisation of Longidorus diadecturus
The Panel on Plant Health performed a pest categorisation of Longidorus diadecturus (Nematoda: Longidoridae) for the EU. The nematode is a well-defined taxon and was described from Ontario, Canada and later reported from some states in the USA. The nematode is not present in the EU. It is regulated by Council Directive 2000/29/EC, listed in Annex I A I as L. diadecturus Eveleigh and Allen. It is a migratory ectoparasitic nematode species puncturing cells of plant roots thereby able to transmit the nepovirus Peach rosette mosaic virus (PRMV). The pest is found in soil associated with plant species belonging to different families. L. diadecturus is able to cause direct damage to plants, but its main damage is caused by vectoring PRMV. Soil is a potential pathway for this nematode for entry into the EU. The nematode is able to survive adverse conditions, but the virus may not persist inside the nematode for extended periods. Climatic conditions in the EU are similar to those found in the countries where the pest is currently present. Hosts of the nematode (and the associated virus) are, e.g. peaches and grapes; those crops are also widely cultivated in the EU. The nematode only moves short distances (around 1 m) but may be spread with soil moving activities. Measures are available to inhibit entry via soil as such. Entry of the nematode with soil attached to plants for planting that are not regulated is possible. L. diadecturus does satisfy all the criteria that are within the remit of EFSA to assess to be regarded as a potential Union quarantine pest
Vitis sp. response to Xylella fastidiosa strain CoDiRO
Following a request from the European Commission, the EFSA Panel on Plant Health assessed a scientific report submitted by the Italian Authorities to the European Commission to support a request to delist Vitissp. from Annex I (âspecified plantsâ) of the Commission Implementing Decision (EU) 2015/789 of 18 May 2015 to prevent the introduction into and the spread within the Union of Xylella fastidiosa (Wells et al.). The report comprised (i) surveys to detect X. fastidiosa in vineyards located in the epidemic zone of CoDiRO with high numbers of diseased olive trees; (ii) inoculation experiments to infect grapevine with a X. fastidiosa isolate âDe Donnoâ from CoDiRO diseased olives; and (iii) vector transmission experiments with X. fastidiosa infective Philaenus spumarius. The Panel acknowledges the difficulties in providing evidence about this hitherto unknown pathogen/vector/host interaction to support the hypothesis that a plant species cannot be infected with a pathogen. Although field surveys to detect X. fastidiosa in grapevine were negative, there was no supporting information on infective vector populations present in the vineyards. Hence absence of infection pressure cannot be excluded. Furthermore the failure to infect grapevine plants either by artificial inoculation or by vector transmission might be due to inoculation conditions not appropriate to induce infections in grapevine. The detection of X. fastidiosa DNA in inoculated grapevine plants even 12 months after inoculation, although localised at the inoculation points, cannot exclude that the DNA amplified by qPCR was from viable cells. The results presented are coherent and provide converging lines of evidence that grapevine (Vitis vinifera) is not a major susceptible host of X. fastidiosa strain CoDiRO. However, from the experimental evidence it is premature to exclude that systemic infections of V.vinifera and Vitissp. occur and that infections at limited foci could serve as a source of inoculum
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