It was thought that the Southern Ocean was relatively free of microplastic contamination; however, recent studies and citizen science projects in the Southern Ocean have reported microplastics in ...deep-sea sediments and surface waters. Here we reviewed available information on microplastics (including macroplastics as a source of microplastics) in the Southern Ocean. We estimated primary microplastic concentrations from personal care products and laundry, and identified potential sources and routes of transmission into the region. Estimates showed the levels of microplastic pollution released into the region from ships and scientific research stations were likely to be negligible at the scale of the Southern Ocean, but may be significant on a local scale. This was demonstrated by the detection of the first microplastics in shallow benthic sediments close to a number of research stations on King George Island. Furthermore, our predictions of primary microplastic concentrations from local sources were five orders of magnitude lower than levels reported in published sampling surveys (assuming an even dispersal at the ocean surface). Sea surface transfer from lower latitudes may contribute, at an as yet unknown level, to Southern Ocean plastic concentrations. Acknowledging the lack of data describing microplastic origins, concentrations, distribution and impacts in the Southern Ocean, we highlight the urgent need for research, and call for routine, standardised monitoring in the Antarctic marine system.
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•The Antarctic marine system is considered pristine compared to other regions.•Microplastics are present in Antarctic waters but available data are scarce.•Local sources of primary microplastic do not explain reported concentrations.•Plastic originating from outside the region may contribute to Antarctic pollution.•Standardised monitoring of microplastic in Antarctic waters is needed urgently.
Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this ...study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion.
Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided.
PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, inhibition of MLL1 in combination with anti-PD-L1 or anti-PD-1 antibody immunotherapy effectively suppresses pancreatic tumor growth in a FasL- and CTL-dependent manner.
The Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 axis play contrasting roles in pancreatic cancer immune surveillance and evasion. Targeting the MLL1-H3K4me3 axis is an effective approach to enhance the efficacy of checkpoint immunotherapy against pancreatic cancer.
Long-term PM
2.5
exposure has been associated with various adverse health outcomes. However, most ground monitors are located in urban areas, leading to a potentially biased representation of true ...regional PM
2.5
levels. To facilitate epidemiological studies, accurate estimates of the spatiotemporally continuous distribution of PM
2.5
concentrations are important. Satellite-retrieved aerosol optical depth (AOD) has been increasingly used for PM
2.5
concentration estimation due to its comprehensive spatial coverage. Nevertheless, previous studies indicated that an inherent disadvantage of many AOD products is their coarse spatial resolution. For instance, the available spatial resolutions of the Moderate Resolution Imaging Spectroradiometer (MODIS) and the Multiangle Imaging SpectroRadiometer (MISR) AOD products are 10 and 17.6 km, respectively. In this paper, a new AOD product with 1 km spatial resolution retrieved by the multi-angle implementation of atmospheric correction (MAIAC) algorithm based on MODIS measurements was used. A two-stage model was developed to account for both spatial and temporal variability in the PM
2.5
–AOD relationship by incorporating the MAIAC AOD, meteorological fields, and land use variables as predictors. Our study area is in the southeastern US centered at the Atlanta metro area, and data from 2001 to 2010 were collected from various sources. The model was fitted annually, and we obtained model fitting
R
2
ranging from 0.71 to 0.85, mean prediction error (MPE) from 1.73 to 2.50 μg m
−3
, and root mean squared prediction error (RMSPE) from 2.75 to 4.10 μg m
−3
. In addition, we found cross-validation
R
2
ranging from 0.62 to 0.78, MPE from 2.00 to 3.01 μgm
−3
, and RMSPE from 3.12 to 5.00 μgm
−3
, indicating a good agreement between the estimated and observed values. Spatial trends showed that high PM
2.5
levels occurred in urban areas and along major highways, while low concentrations appeared in rural or mountainous areas. Our time-series analysis showed that, for the 10-year study period, the PM
2.5
levels in the southeastern US have decreased by ∼20 %. The annual decrease has been relatively steady from 2001 to 2007 and from 2008 to 2010 while a significant drop occurred between 2007 and 2008. An observed increase in PM
2.5
levels in year 2005 is attributed to elevated sulfate concentrations in the study area in warm months of 2005.
Signaling via pattern recognition receptors (PRRs) expressed on professional antigen presenting cells, such as dendritic cells (DCs), is crucial to the fate of engulfed microbes. Among the many PRRs ...expressed by DCs are Toll-like receptors (TLRs) and C-type lectins such as DC-SIGN. DC-SIGN is targeted by several major human pathogens for immune-evasion, although its role in intracellular routing of pathogens to autophagosomes is poorly understood. Here we examined the role of DC-SIGN and TLRs in evasion of autophagy and survival of Porphyromonas gingivalis in human monocyte-derived DCs (MoDCs). We employed a panel of P. gingivalis isogenic fimbriae deficient strains with defined defects in Mfa-1 fimbriae, a DC-SIGN ligand, and FimA fimbriae, a TLR2 agonist. Our results show that DC-SIGN dependent uptake of Mfa1+P. gingivalis strains by MoDCs resulted in lower intracellular killing and higher intracellular content of P. gingivalis. Moreover, Mfa1+P. gingivalis was mostly contained within single membrane vesicles, where it survived intracellularly. Survival was decreased by activation of TLR2 and/or autophagy. Mfa1+P. gingivalis strain did not induce significant levels of Rab5, LC3-II, and LAMP1. In contrast, P. gingivalis uptake through a DC-SIGN independent manner was associated with early endosomal routing through Rab5, increased LC3-II and LAMP-1, as well as the formation of double membrane intracellular phagophores, a characteristic feature of autophagy. These results suggest that selective engagement of DC-SIGN by Mfa-1+P. gingivalis promotes evasion of antibacterial autophagy and lysosome fusion, resulting in intracellular persistence in myeloid DCs; however TLR2 activation can overcome autophagy evasion and pathogen persistence in DCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•GraphVar is a user-friendly toolbox for comprehensive graph analyses of brain connectivity.•GraphVar combines features across multiple current toolboxes without resorting to code.•GraphVar entails ...an interactive viewer for results exploration.•GraphVar will make graph theoretical methods more accessible for a broader audience.
Graph theory provides a powerful and comprehensive formalism of global and local topological network properties of complex structural or functional brain connectivity. Software packages such as the Brain-Connectivity-Toolbox have contributed to graph theory's increasing popularity for characterization of brain networks. However, comparably comprehensive packages are command-line based and require programming experience; this precludes their use by users without a computational background, whose research would otherwise benefit from graph-theoretical methods.
“GraphVar” is a user-friendly GUI-based toolbox for comprehensive graph-theoretical analyses of brain connectivity, including network construction and characterization, statistical analysis on network topological measures, network based statistics, and interactive exploration of results.
GraphVar provides a comprehensive collection of graph analysis routines for analyses of functional brain connectivity in one single toolbox by combining features across multiple currently available toolboxes, such as the Brain Connectivity Toolbox, the Graph Analysis Toolbox, and the Network Based Statistic Toolbox (BCT, Rubinov and Sporns, 2010; GAT, Hosseini et al., 2012; NBS, Zalesky et al., 2010). GraphVar was developed under the GNU General Public License v3.0 and can be downloaded at www.rfmri.org/graphvar or www.nitrc.org/projects/graphvar.
By combining together features across multiple toolboxes, GraphVar will allow comprehensive graph-theoretical analyses in one single toolbox without resorting to code.
GraphVar will make graph theoretical methods more accessible for a broader audience of neuroimaging researchers.
Ecosystem process rates typically increase after plant invasion, but the extent to which this is driven by (i) changes in productivity, (ii) exotic species' traits, or (iii) novel (non-coevolved) ...biotic interactions has never been quantified. We created communities varying in exotic plant dominance, plant traits, soil biota, and invertebrate herbivores and measured indicators of carbon cycling. Interactions with soil biota and herbivores were the strongest drivers of exotic plant effects, particularly on measures of soil carbon turnover. Moreover, plant traits related to growth and nutrient acquisition explained differences in the ways that exotic plants interacted with novel biota compared with natives. We conclude that novel biological interactions with exotic species are a more important driver of ecosystem transformation than was previously recognized.
One hallmark example of a link between global topological network properties of complex functional brain connectivity and cognitive performance is the finding that general intelligence may depend on ...the efficiency of the brain's intrinsic functional network architecture. However, although this association has been featured prominently over the course of the last decade, the empirical basis for this broad association of general intelligence and global functional network efficiency is quite limited. In the current study, we set out to replicate the previously reported association between general intelligence and global functional network efficiency using the large sample size and high quality data of the Human Connectome Project, and extended the original study by testing for separate association of crystallized and fluid intelligence with global efficiency, characteristic path length, and global clustering coefficient. We were unable to provide evidence for the proposed association between general intelligence and functional brain network efficiency, as was demonstrated by van den Heuvel et al. (2009), or for any other association with the global network measures employed. More specifically, across multiple network definition schemes, ranging from voxel-level networks to networks of only 100 nodes, no robust associations and only very weak non-significant effects with a maximal R2 of 0.01 could be observed. Notably, the strongest (non-significant) effects were observed in voxel-level networks. We discuss the possibility that the low power of previous studies and publication bias may have led to false positive results fostering the widely accepted notion of general intelligence being associated to functional global network efficiency.
With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No ...specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering.
The aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor--AT2R--agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses.
Treatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation.
Collectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed.
The manuscript assesses the current and expected future global drivers of Southern Ocean (SO) ecosystems. Atmospheric ozone depletion over the Antarctic since the 1970s, has been a key driver, ...resulting in springtime cooling of the stratosphere and intensification of the polar vortex, increasing the frequency of positive phases of the Southern Annular Mode (SAM). This increases warm air-flow over the East Pacific sector (Western Antarctic Peninsula) and cold air flow over the West Pacific sector. SAM as well as El Niño Southern Oscillation events also affect the Amundsen Sea Low leading to either positive or negative sea ice anomalies in the west and east Pacific sectors, respectively. The strengthening of westerly winds is also linked to shoaling of deep warmer water onto the continental shelves, particularly in the East Pacific and Atlantic sectors. Air and ocean warming has led to changes in the cryosphere, with glacial and ice sheet melting in both sectors, opening up new ice free areas to biological productivity, but increasing seafloor disturbance by icebergs. The increased melting is correlated with a salinity decrease particularly in the surface 100 m. Such processes could increase the availability of iron, which is currently limiting primary production over much of the SO. Increasing CO
2
is one of the most important SO anthropogenic drivers and is likely to affect marine ecosystems in the coming decades. While levels of many pollutants are lower than elsewhere, persistent organic pollutants (POPs) and plastics have been detected in the SO, with concentrations likely enhanced by migratory species. With increased marine traffic and weakening of ocean barriers the risk of the establishment of non-indigenous species is increased. The continued recovery of the ozone hole creates uncertainty over the reversal in sea ice trends, especially in the light of the abrupt transition from record high to record low Antarctic sea ice extent since spring 2016. The current rate of change in physical and anthropogenic drivers is certain to impact the Marine Ecosystem Assessment of the Southern Ocean (MEASO) region in the near future and will have a wide range of impacts across the marine ecosystem.
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