118 research outputs found
Mal Mediates TLR-Induced Activation of CREB and Expression of IL-10
TLRs initiate immune responses by direct detection of molecular motifs that distinguish invading microbes from host cells. Five
intracellular adaptor proteins, each containing a Toll/IL-1R (TIR) domain, are used by TLRs and play key roles in dictating gene
expression patterns that are tailored to the invader. Such gene expression is mediated by transcription factors, and although TIR
adaptor-induced activation of NF-kB and the IFN regulatory factors have been intensively studied, there is a dearth of information
on the role of TIR adaptors in regulating CREB. In this paper, we describe a role for the TIR adaptor Mal in enhancing
activation of CREB. Mal-deficient murine bone marrow-derived macrophages show a loss in responsiveness to TLR2 and TLR4
ligands with respect to activation of CREB. Mal-deficient cells also fail to express the CREB-responsive genes IL-10 and cyclooxygenase
2 in response to Pam2Cys-Ser-(Lys)4 and LPS. We reveal that Mal-mediated activation of CREB is dependent on
Pellino3 and TNFR-associated factor 6, because CREB activation is greatly diminished in Pellino3 knockdown cells and TNFRassociated
factor 6-deficient cells. We also demonstrate the importance of p38 MAPK in this pathway with the p38 inhibitor
SB203580 abolishing activation of CREB in murine macrophages. MAPK-activated protein kinase 2 (MK2), a substrate for p38
MAPK, is the likely downstream mediator of p38 MAPK in this pathway, because Mal is shown to activate MK2 and inhibition of
MK2 decreases TLR4-induced activation of CREB. Overall, these studies demonstrate a new role for Mal as a key upstream
regulator of CREB and as a contributor to the expression of both pro- and anti-inflammatory gen
Mal Mediates TLR-Induced Activation of CREB and Expression of IL-10
TLRs initiate immune responses by direct detection of molecular motifs that distinguish invading microbes from host cells. Five
intracellular adaptor proteins, each containing a Toll/IL-1R (TIR) domain, are used by TLRs and play key roles in dictating gene
expression patterns that are tailored to the invader. Such gene expression is mediated by transcription factors, and although TIR
adaptor-induced activation of NF-kB and the IFN regulatory factors have been intensively studied, there is a dearth of information
on the role of TIR adaptors in regulating CREB. In this paper, we describe a role for the TIR adaptor Mal in enhancing
activation of CREB. Mal-deficient murine bone marrow-derived macrophages show a loss in responsiveness to TLR2 and TLR4
ligands with respect to activation of CREB. Mal-deficient cells also fail to express the CREB-responsive genes IL-10 and cyclooxygenase
2 in response to Pam2Cys-Ser-(Lys)4 and LPS. We reveal that Mal-mediated activation of CREB is dependent on
Pellino3 and TNFR-associated factor 6, because CREB activation is greatly diminished in Pellino3 knockdown cells and TNFRassociated
factor 6-deficient cells. We also demonstrate the importance of p38 MAPK in this pathway with the p38 inhibitor
SB203580 abolishing activation of CREB in murine macrophages. MAPK-activated protein kinase 2 (MK2), a substrate for p38
MAPK, is the likely downstream mediator of p38 MAPK in this pathway, because Mal is shown to activate MK2 and inhibition of
MK2 decreases TLR4-induced activation of CREB. Overall, these studies demonstrate a new role for Mal as a key upstream
regulator of CREB and as a contributor to the expression of both pro- and anti-inflammatory gen
A poxviral homolog of the Pellino protein inhibits Toll and Toll-like receptor signalling
Toll-like receptor (TLR) signalling pathways constitute an evolutionarily conserved
component of the host immune response to pathogenic infection. Here, we describe the
ability of a virally encoded form of the Pellino protein to inhibit Toll- and TLR-mediated
activation of downstream Rel family transcription factors. In addition to inhibiting drosomycin
promoter activation by Spa¨ tzle in Drosophila melanogaster cells, viral Pellino
attenuates the activation of NF-jB by TLR signalling components and by the TLR4 ligand,
LPS, in human cells. We propose that viral Pellino, like mammalian Pellinos, contains a
forkhead-associated domain but differs from the mammalian forms in that it lacks a
complete and functional RING-like domain. We produce a homology model and present
experimental data to support this model by demonstrating that, like mammalian Pellinos,
viral Pellino can interact with IRAK-1 via its forkhead-associated domain, whereas unlike
its mammalian counterparts, it fails to post-translationally modify IRAK-1. Furthermore,
we demonstrate that viral Pellino can functionally antagonise the activity of human
Pellino3S. Thus, our findings identify potential immunoevasive capabilities possessed by a
poxviral homolog of the Pellino protein and add growing evidence for a likely role for
Pellino proteins in Toll and TLR signalling
Defining the Realized Niche of the Two Major Clades of \u3ci\u3eTrichodesmium\u3c/i\u3e: A Study on the West Florida Shelf
The cyanobacterium Trichodesmium plays an essential role supporting ocean productivity by relieving nitrogen limitation via dinitrogen (N-2) fixation. The two common Trichodesmium clades, T. erythraeum and T. thiebautii, are both observed in waters along the West Florida Shelf (WFS). We hypothesized that these taxa occupy distinct realized niches, where T. thiebautii is the more oceanic clade. Samples for DNA and water chemistry analyses were collected on three separate WFS expeditions (2015, 2018, and 2019) spanning multiple seasons; abundances of the single copy housekeeping gene rnpB from both clades were enumerated via quantitative PCR. We conducted a suite of statistical analyses to assess Trichodesmium clade abundances in the context of the physicochemical data. We observed a consistent coastal vs. open ocean separation of the two clades: T. erythraeum was found in shallow waters where the concentrations of dissolved iron (dFe) and the groundwater tracer Ba were significantly higher, while T. thiebautii abundance was positively correlated with water column depth. The Loop Current intrusion in 2015 with entrained Missisippi River water brought higher dFe and elevated abundance of both clades offshore of the 50 m isobath, suggesting that both clades are subject to Fe limitation on the outer shelf. Whereas, previous work has observed that T. thiebautii is more abundant than T. erythraeum in open ocean surface waters, this is the first study to examine Trichodesmium niche differentiation in a coastal environment. Understanding the environmental niches of these two key taxa bears important implications for their contributions to global nitrogen and carbon cycling and their response to global climate change
Seabed geomorphology: a two-part classification system
The BGS has developed a two-
part classification system
(‘Morphology’ and ‘Geomorphology’)
to facilitate work on a new ‘S
eabed Geomorphology’ mapping initia
tive, and this classification
system is the focus of this report. As stated in
the Foreword, the rationale
and the basic framework
of the classification system were conceived and es
tablished within BGS, but
recent collaboration
within the
MAREANO
-Norway,
INFOMAR
-Ireland, and
MAREMAP
-UK (MIM) partnership
has led to significant improvement of the classifi
cation system, and this report. To further support
this effort, existing BGS GIS tools (SIGMA) ha
ve been adapted to apply this two-part
classification system for more efficient geom
orphological mapping in the marine environment.
This report:
provides a brief background on seabed mapping
and characterisation, as well as how this
science has been addressed
historically within BGS;
describes the current motiva
tion to conduct seabed geom
orphological mapping, and the
requirement for a new set of t
ools to facilitate this work;
describes the logical framework that
underpins the classification system;
outlines the attributes of the classification
system, how it can be applied, and discusses
the advantages and limitations of the approach.
It is anticipated that through testing and usage,
the classification syst
em will be revised and
improved over time, with updated versions released
through MIM partnershi
p. It is also planned
that a further ‘user guide’ report
will be produced for the classifi
cation system and the GIS tools,
including thematic details (e.g.
background information on ‘coastal’
or ‘glacial’ features) and a
feature glossary
Tracing differences in iron supply to the Mid-Atlantic Ridge valley between hydrothermal vent sites: implications for the addition of iron to the deep ocean
Supply of iron (Fe) to the surface ocean supports primary productivity, and while hydrothermal input of Fe to the deep ocean is known
to be extensive it remains poorly constrained. Global estimates of hydrothermal Fe supply rely on using dissolved Fe (dFe) to
excess He (xs3He) ratios to upscale fluxes, but observational constraints on dFe/xs3He may be sensitive to
assumptions linked to sampling and interpolation. We examined the variability in dFe/xs3He using two methods of estimation, for
four vent sites with different geochemistry along the Mid-Atlantic Ridge. At both Rainbow and TAG, the plume was sampled repeatedly and the range of
dFe/xs3He was 4 to 63 and 4 to 87 nmol:fmol, respectively, primarily due to differences in plume age. To account for background
xs3He and shifting plume position, we calibrated He values using contemporaneous dissolved Mn (dMn). Applying this
approach more widely, we found dFe/xs3He ratios of 12, 4–8, 4–44, and 4–86 nmol fmol−1 for the Menez Gwen, Lucky
Strike, Rainbow, and TAG hydrothermal vent sites, respectively. Differences in plume dFe/xs3He across sites were not simply
related to the vent endmember Fe and He fluxes. Within 40 km of the vents, the dFe/xs3He ratios decreased to
3–38 nmol fmol−1, due to the precipitation and subsequent settling of particulates. The ratio of colloidal Fe to dFe was
consistently higher (0.67–0.97) than the deep N. Atlantic (0.5) throughout both the TAG and Rainbow plumes, indicative of Fe exchange
between dissolved and particulate phases. Our comparison of TAG and Rainbow shows there is a limit to the amount of hydrothermal Fe released
from vents that can form colloids in the rising plume. Higher particle loading will enhance the longevity of the Rainbow hydrothermal plume within
the deep ocean assuming particles undergo continual dissolution/disaggregation. Future studies examining the length of plume pathways required to
escape the ridge valley will be important in determining Fe supply from slow spreading mid-ocean ridges to the deep ocean, along with the
frequency of ultramafic sites such as Rainbow. Resolving the ridge valley bathymetry and accounting for variability in vent sources in global
biogeochemical models will be key to further constraining the hydrothermal Fe flux.</p
Tracing differences in iron supply to the Mid-Atlantic Ridge valley between hydrothermal vent sites: implications for the addition of iron to the deep ocean
Supply of iron (Fe) to the surface ocean supports primary productivity, and while hydrothermal input of Fe to the deep ocean is known to be extensive it remains poorly constrained. Global estimates of hydrothermal Fe supply rely on using dissolved Fe (dFe) to excess He (xs³He) ratios to upscale fluxes, but observational constraints on dFe/xs³He may be sensitive to assumptions linked to sampling and interpolation. We examined the variability in dFe/xs³He using two methods of estimation, for four vent sites with different geochemistry along the Mid-Atlantic Ridge. At both Rainbow and TAG, the plume was sampled repeatedly and the range of dFe/xs³He was 4 to 63 and 4 to 87 nmol:fmol, respectively, primarily due to differences in plume age. To account for background xs³He and shifting plume position, we calibrated He values using contemporaneous dissolved Mn (dMn). Applying this approach more widely, we found dFe/xs³He ratios of 12, 4–8, 4–44, and 4–86 nmol fmol−1 for the Menez Gwen, Lucky Strike, Rainbow, and TAG hydrothermal vent sites, respectively. Differences in plume dFe/xs³He across sites were not simply related to the vent endmember Fe and He fluxes. Within 40 km of the vents, the dFe/xs³He ratios decreased to 3–38 nmol fmol−1, due to the precipitation and subsequent settling of particulates. The ratio of colloidal Fe to dFe was consistently higher (0.67–0.97) than the deep N. Atlantic (0.5) throughout both the TAG and Rainbow plumes, indicative of Fe exchange between dissolved and particulate phases. Our comparison of TAG and Rainbow shows there is a limit to the amount of hydrothermal Fe released from vents that can form colloids in the rising plume. Higher particle loading will enhance the longevity of the Rainbow hydrothermal plume within the deep ocean assuming particles undergo continual dissolution/disaggregation. Future studies examining the length of plume pathways required to escape the ridge valley will be important in determining Fe supply from slow spreading mid-ocean ridges to the deep ocean, along with the frequency of ultramafic sites such as Rainbow. Resolving the ridge valley bathymetry and accounting for variability in vent sources in global biogeochemical models will be key to further constraining the hydrothermal Fe flux
Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease
© 2020, The Author(s). Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation
APOE ε2 resilience for Alzheimer’s disease is mediated by plasma lipid species: Analysis of three independent cohort studies
Introduction
The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer\u27s disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood.
Methods
We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer\u27s Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species.
Results
A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer\u27s disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively.
Discussion
Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer\u27s disease and as such represent a potential therapeutic target
Early paleocene paleoceanography and export productivity in the Chicxulub crater
The Chicxulub impact caused a crash in productivity in the world''s oceans which contributed to the extinction of ~75% of marine species. In the immediate aftermath of the extinction, export productivity was locally highly variable, with some sites, including the Chicxulub crater, recording elevated export production. The long-term transition back to more stable export productivity regimes has been poorly documented. Here, we present elemental abundances, foraminifer and calcareous nannoplankton assemblage counts, total organic carbon, and bulk carbonate carbon isotope data from the Chicxulub crater to reconstruct changes in export productivity during the first 3 Myr of the Paleocene. We show that export production was elevated for the first 320 kyr of the Paleocene, declined from 320 kyr to 1.2 Myr, and then remained low thereafter. A key interval in this long decline occurred 900 kyr to 1.2 Myr post impact, as calcareous nannoplankton assemblages began to diversify. This interval is associated with fluctuations in water column stratification and terrigenous flux, but these variables are uncorrelated to export productivity. Instead, we postulate that the turnover in the phytoplankton community from a post-extinction assemblage dominated by picoplankton (which promoted nutrient recycling in the euphotic zone) to a Paleocene pelagic community dominated by relatively larger primary producers like calcareous nannoplankton (which more efficiently removed nutrients from surface waters, leading to oligotrophy) is responsible for the decline in export production in the southern Gulf of Mexico. © 2021. American Geophysical Union. All Rights Reserved
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