128 research outputs found
Ongoing Oxidative Stress Causes Subclinical Neuronal Dysfunction in the Recovery Phase of EAE
Most multiple sclerosis (MS) patients develop over time a secondary
progressive disease course, characterized histologically by axonal loss and
atrophy. In early phases of the disease, focal inflammatory demyelination
leads to functional impairment, but the mechanism of chronic progression in MS
is still under debate. Reactive oxygen species generated by invading and
resident central nervous system (CNS) macrophages have been implicated in
mediating demyelination and axonal damage, but demyelination and
neurodegeneration proceed even in the absence of obvious immune cell
infiltration, during clinical recovery in chronic MS. Here, we employ
intravital NAD(P)H fluorescence lifetime imaging to detect functional NADPH
oxidases (NOX1â4, DUOX1, 2) and, thus, to identify the cellular source of
oxidative stress in the CNS of mice affected by experimental autoimmune
encephalomyelitis (EAE) in the remission phase of the disease. This directly
affects neuronal function in vivo, as monitored by cellular calcium levels
using intravital FRETâFLIM, providing a possible mechanism of disease
progression in MS
Low-Density Granulocytes Are a Novel Immunopathological Feature in Both Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder
Objective: To investigate whether low-density granulocytes (LDGs) are an immunophenotypic feature of patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD).
Methods: Blood samples were collected from 20 patients with NMOSD and 17 patients with MS, as well as from 15 patients with Systemic Lupus Erythematosus (SLE) and 23 Healthy Donors (HD). We isolated peripheral blood mononuclear cells (PBMCs) with density gradient separation and stained the cells with antibodies against CD14, CD15, CD16, and CD45, and analyzed the cells by flow cytometry or imaging flow cytometry. We defined LDGs as CD14-CD15(high) and calculated their share in total PBMC leukocytes (CD45+) as well as the share of CD16(hi) LDGs. Clinical data on disease course, medication, and antibody status were obtained.
Results: LDGs were significantly more common in MS and NMOSD than in HDs, comparable to SLE samples (median values HD 0.2%, MS 0.9%, NMOSD 2.1%, SLE 4.3%). 0/23 of the HDs, but 17/20 NMOSD and 11/17 MS samples as well as 13/15 SLE samples had at least 0.7 % LDGs. NMOSD patients without continuous immunosuppressive treatment had significantly more LDGs compared to their treated counterparts. LDG nuclear morphology ranged from segmented to rounded, suggesting a heterogeneity within the group.
Conclusion: LDGs are a feature of the immunophenotype in some patients with MS and NMOSD
Bulk gravitons from a cosmological brane
We investigate the emission of gravitons by a cosmological brane into an Anti
de Sitter five-dimensional bulk spacetime. We focus on the distribution of
gravitons in the bulk and the associated production of `dark radiation' in this
process. In order to evaluate precisely the amount of dark radiation in the
late low-energy regime, corresponding to standard cosmology, we study
numerically the emission, propagation and bouncing off the brane of bulk
gravitons.Comment: 27 pages, 5 figures, minor corrections. Final versio
NAD(P)H fluorescence lifetime imaging of live intestinal nematodes reveals metabolic crosstalk between parasite and host
Infections with intestinal nematodes have an equivocal impact: they represent a burden for human health and animal husbandry, but, at the same time, may ameliorate auto-immune diseases due to the immunomodulatory effect of the parasites. Thus, it is key to understand how intestinal nematodes arrive and persist in their luminal niche and interact with the host over long periods of time. One basic mechanism governing parasite and host cellular and tissue functions, metabolism, has largely been neglected in the study of intestinal nematode infections. Here we use NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate) fluorescence lifetime imaging of explanted murine duodenum infected with the natural nematode Heligmosomoides polygyrus and define the link between general metabolic activity and possible metabolic pathways in parasite and host tissue, during acute infection. In both healthy and infected host intestine, energy is effectively produced, mainly via metabolic pathways resembling oxidative phosphorylation/aerobic glycolysis features. In contrast, the nematodes shift their energy production from balanced fast anaerobic glycolysis-like and effective oxidative phosphorylation-like metabolic pathways, towards mainly anaerobic glycolysis-like pathways, back to oxidative phosphorylation/aerobic glycolysis-like pathways during their different life cycle phases in the submucosa versus the intestinal lumen. Additionally, we found an increased NADPH oxidase (NOX) enzymes-dependent oxidative burst in infected intestinal host tissue as compared to healthy tissue, which was mirrored by a similar defense reaction in the parasites. We expect that, the here presented application of NAD(P)H-FLIM in live tissues constitutes a unique tool to study possible shifts between metabolic pathways in host-parasite crosstalk, in various parasitic intestinal infections
Cosmology of a brane radiating gravitons into the extra dimension
We study in a self-consistent way the impact of the emission of bulk
gravitons on the (homogeneous) cosmology of a three-brane embedded in a
five-dimensional spacetime. In the low energy regime, we recover the well known
result that the bulk affects the Friedmann equation only via a radiation-like
term \C/a^4, called dark or Weyl radiation. By contrast, in the high energy
regime, we find that the Weyl parameter \C is no longer constant but instead
grows very rapidly as \C\propto a^4. As a consequence, the value of \C
today is not a free parameter as usually considered but is a fixed number,
which, generically, depends only on the number of relativistic degrees of
freedom at the high/low energy transition. Our estimated amount of Weyl
radiation satisfies the present nucleosynthesis bounds.Comment: 12 page
In the Right Place, at the Right Time: Spatiotemporal Conditions Determining Plasma Cell Survival and Function
Plasma cells (PCs), the B lineage cells responsible for producing and secreting antibodies (Abs), are critical cellular components of the humoral immune system. While most of the antibody-secreting cells in the body have a rather short lifetime of a few days, some of them can become long-lived and persist in the body over the entire life span of an individual. The majority of these long-lived plasma cells secretes protective antibodies against pathogens, and are thereby crucial for the humoral component of immunological memory. The generation of these protective antibody-secreting cells can be triggered by an exposure to pathogens, and also by vaccination. Although the majority of plasma cells are protective, sometimes long-lived plasma cells produce autoreactive antibodies, which contribute to the pathogenesis and perpetuation of chronic autoimmune diseases, including lupus erythematosus, rheumatoid arthritis, or multiple sclerosis. In order to promote the formation of protective antibody-secreting cells and to target pathogenic plasma cells, it is crucial to understand the signals which promote their longevity and allow them to exert their function. In recent years, it has become clear that plasma cells depend on extrinsic factors for their survival, leading to the concept that certain tissue microenvironments promote plasma cell retention and longevity. However, these niches are not static structures, but also have dynamic features with respect to their cellular composition. Here, we review what is known about the molecular and cellular composition of the niches, and discuss the impact of dynamic changes within these microenvironments on plasma cell function. As plasma cell metabolism is tightly linked to their function, we present new tools, which will allow us to analyze metabolic parameters in the plasma cell niches in vivo over time
Application to the Analysis of Germinal Center Reactions In Vivo
Simultaneous detection of multiple cellular and molecular players in their
native environment, one of the keys to a full understanding of immune
processes, remains challenging for in vivo microscopy. Here, we present a
synergistic strategy for spectrally multiplexed in vivo imaging composed of
(i) triple two-photon excitation using spatiotemporal synchronization of two
femtosecond lasers, (ii) a broad set of fluorophores with emission ranging
from blue to near infrared, (iii) an effective spectral unmixing algorithm.
Using our approach, we simultaneously excite and detect seven fluorophores
expressed in distinct cellular and tissue compartments, plus second harmonics
generation from collagen fibers in lymph nodes. This enables us to visualize
the dynamic interplay of all the central cellular players during germinal
center reactions. While current in vivo imaging typically enables recording
the dynamics of 4 tissue components at a time, our strategy allows a more
comprehensive analysis of cellular dynamics involving 8 single-labeled
compartments. It enables to investigate the orchestration of multiple cellular
subsets determining tissue function, thus, opening the way for a mechanistic
understanding of complex pathophysiologic processes in vivo. In the future,
the design of transgenic mice combining a larger spectrum of fluorescent
proteins will reveal the full potential of our method
Dimension in a Radiative Stellar Atmosphere
Dimensional scales are examined in an extended 3+1 Vaidya atmosphere
surrounding a Schwarzschild source. At one scale, the Vaidya null fluid
vanishes and the spacetime contains only a single spherical 2-surface. Both of
these behaviors can be addressed by including higher dimensions in the
spacetime metric.Comment: to appear in Gen. Rel. Gra
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Conformance Improvement Using Gels
This research project had two objectives. The first objective was to identify gel compositions and conditions that substantially reduce flow through fractures that allow direct channeling between wells, while leaving secondary fractures open so that high fluid injection and production rates can be maintained. The second objective was to optimize treatments in fractured production wells, where the gel must reduce permeability to water much more than that to oil
Walking to School: Incidental Physical Activity in the Daily Occupations of Australian Children
Children's participation in physical activity is declining, and nowhere is this more apparent than in the incidental activity of walking to school_ The aim of this pilot study was to examine the extent to which Australian children walked to and from primary school, and to survey parents to identify factors influencing this behaviour. Parents of 164 students in Grades I-7 (mean age 9.1 +/- 2.02 years) from a primary school comprising 360 students responded to a questionnaire regarding psychosocial and environmental factors thought to influence the means by which their children went to and from school. Results indicated that parent perception of the importance of physical activity, parents' individual history of transport to school as well as distance from school were the most statistically significant factors determining children's involvement in walking to and from school. The results of this study highlight the attitudes and experiences of parents in determining the extent to which children are involved in non-motorized access to school. Also implicated are organizational policies about geographical school regions. While this study is limited to one school community, further study is recommended with others to better confirm findings by examining socioeconomic, geographic and policy variables. Occupational therapists are challenged to examine ways in which incidental physical activity can be increased in the lives of young children
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