Upon tissue injury, high m.w. hyaluronan (HA), a ubiquitously distributed extracellular matrix component, is broken down into lower m.w. (LMW) fragments, which in turn activate an innate immune ...response. In doing so, LMW HA acts as an endogenous danger signal alerting the immune system of a breach in tissue integrity. In this report, we demonstrate that LMW HA activates the innate immune response via TLR-2 in a MyD88-, IL-1R-associated kinase-, TNFR-associated factor-6-, protein kinase Czeta-, and NF-kappaB-dependent pathway. Furthermore, we show that intact high m.w. HA can inhibit TLR-2 signaling. Finally, we demonstrate that LMW HA can act as an adjuvant promoting Ag-specific T cell responses in vivo in wild-type but not TLR-2(null) mice.
Research and development work for about one decade have demonstrated many unique thermal spray coating properties, particularly for oxide ceramic coatings by using suspensions of fine powders as ...feedstock in APS and HVOF processes. Some particular advantages are direct feeding of fine nano- and submicron-scale particles avoiding special feedstock powder preparation, ability to produce coating thicknesses ranging from 10 to 50 µm, homogeneous microstructure with less anisotropy and lower surface roughness compared to conventional coatings, possibility of retention of the initial crystalline phases, and others. This paper discusses the main aspects of thermal spraying with suspensions which have been taken into account in order to produce these coatings on an economical way. The economic efficiency of the process depends on the availability of suitable additional system components (suspension feeder, injectors), on the development and handling of stable suspensions, as well as on the high process stability for acceptance at industrial scale. Special focus is made on the development and processability of highly concentrated water-based suspensions. While costs and operational safety clearly speak for use of water as a liquid media for preparing suspensions on an industrial scale, its use is often critically discussed due to the required higher heat input during spraying compared to alcoholic suspensions.
Two experimental agglomerated and sintered (a&s) feedstock powders were prepared, in order to reveal the role of WC addition on the microstructure, hardness, and the abrasion resistance of ...HVOF-sprayed Cr3C2-NiCr coatings. These powders contained 10wt.% of sub-micron WC, 20 or 10wt.% of nickel binder, and Cr3C2 as balance. Experimental coatings were deposited by a liquid fueled high velocity oxygen-fuel (HVOF) spray process and subsequently heat treated at 800 °C for 8h to simulate elevated temperature service conditions. The microstructures of the powders and coatings were studied by SEM and X-ray diffraction, and the hardnesses of coatings were probed by means of micro and nanoindentation. In addition, the high stress abrasion resistance was tested in a temperature range from room temperature up to 800 °C. The microstructural characterization of the coatings displayed the presence of WC and tungsten containing Cr3C2 grains. The coating hardness increased after heat treatment, which stemmed from precipitation of secondary carbides and solid solution strengthening of the binder by tungsten. In addition, the study revealed that both experimental coatings have high wear resistance at room and elevated temperatures.
Depression is a common, though heterogenous, comorbidity in late-onset Alzheimer's Disease (LOAD) patients. In addition, individuals with depression are at greater risk to develop LOAD. In previous ...work, we demonstrated shared genetic etiology between depression and LOAD. Collectively, these previous studies suggested interactions between depression and LOAD. However, the underpinning genetic heterogeneity of depression co-occurrence with LOAD, and the various genetic etiologies predisposing depression in LOAD, are largely unknown.
Major Depressive Disorder (MDD) genome-wide association study (GWAS) summary statistics were used to create polygenic risk scores (PRS). The Religious Orders Society and Rush Memory and Aging Project (ROSMAP,
= 1,708) and National Alzheimer's Coordinating Center (NACC,
= 10,256) datasets served as discovery and validation cohorts, respectively, to assess the PRS performance in predicting depression onset in LOAD patients.
The PRS showed marginal results in standalone models for predicting depression onset in both ROSMAP (AUC = 0.540) and NACC (AUC = 0.527). Full models, with baseline age, sex, education, and
allele count, showed improved prediction of depression onset (ROSMAP AUC: 0.606, NACC AUC: 0.581). In time-to-event analysis, standalone PRS models showed significant effects in ROSMAP (
= 0.0051), but not in NACC cohort. Full models showed significant performance in predicting depression in LOAD for both datasets (
< 0.001 for all).
This study provided new insights into the genetic factors contributing to depression onset in LOAD and advanced our knowledge of the genetics underlying the heterogeneity of depression in LOAD. The developed PRS accurately predicted LOAD patients with depressive symptoms, thus, has clinical implications including, diagnosis of LOAD patients at high-risk to develop depression for early anti-depressant treatment.
Coatings prepared from chromia-rich (Al,Cr)
2
O
3
solid solution (ss) feedstock powders are intended to improve the properties of Cr
2
O
3
coatings, but are rarely studied so far. In this work, the ...processability of a commercial (Al,Cr)
2
O
3
solid solution (ss) powder containing 78 wt.% Cr
2
O
3
by atmospheric plasma spraying (APS), the corresponding coating microstructures and properties were investigated. Possible further improvements were expected by blending with 2, 23 and 54 wt.% TiO
x
powder. For comparison, plain Cr
2
O
3
and TiO
x
coatings were studied as well. The microstructures were analyzed using SEM, EDS and XRD measurements. Hardness (HV0.3) was measured, as well as the dry unidirectional sliding wear resistance and the abrasion wear resistance (ASTM G65). Moreover, the corrosion and electrical insulating properties were measured. The (Al,Cr)
2
O
3
ss showed only a small change of the composition, and the formation of
γ
-Al
2
O
3
, as found for alumina-rich (Al,Cr)
2
O
3
ss powders, was avoided. Compared to the plain chromia coating, some improvements of the processability and coating properties for the ss (Al,Cr)
2
O
3
coating were found. The most balanced coating performance was achieved by blending the ss (Al,Cr)
2
O
3
with 2 wt.% TiO
x
, as this coating showed both a high sliding and abrasion wear resistance, in combination with a high corrosion resistance.
The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al. identified the association between the length of TOMM40 ...poly-T with the risk and age of onset of late-onset Alzheimer's disease (LOAD). Following the original discovery, additional studies found associations between the TOMM40 poly-T and LOAD-related phenotypes independent of APOE genotypes, while others did not replicate these associations. Furthermore, the identity of the TOMM40 poly-T risk allele has been controversial between different LOAD-related phenotypes. Here, we propose a framework to address the conflicting findings with respect to the TOMM40 poly-T allele associations with LOAD phenotypes and their functional effects. The framework is used to interpret previous studies as means to gain insights regarding the nature of the risk allele, very long versus short. We suggest that the identity of the TOMM40 poly-T risk allele depends on the phenotype being evaluated, the ages of the study subjects at the time of assessment, and the context of the APOE genotypes. In concluding remarks, we outline future studies that will inform the mechanistic interpretation of the genetic data.
•TOMM40 poly-T has autonomous associations with late-onset Alzheimer's disease–related phenotypes.•The direction of the TOMM40 poly-T effects are influenced by interactions with APOE.•The identity of the TOMM40 poly-T risk allele depends on the phenotype being evaluated and the ages of the study subjects.
Background:
Both leisure activities and the ε4 allele of the apolipoprotein E (
APOE
ε4) have been shown to affect cognitive health. We aimed to determine whether engagement in leisure activities ...protects against
APOE
ε4-related cognitive decline.
Methods:
We used the cohort data from the Chinese Longitudinal Healthy Longevity Survey. A total of 3,017 participants (mean age of 77.0 years, SD = 9.0; 49.3% female) from 23 provinces of China were recruited in 2008 and were reinterviewed in 2014. We assessed cognitive function using the Mini-Mental State Examination (MMSE). We calculated cognitive decline using subtraction of the MMSE score of each participant in 2008 and 2014. We genotyped a number of
APOE
ε4 alleles for each participant at baseline and determined the Index of Leisure Activities (ILAs) by summing up the frequency of nine types of typical activities in productive, social, and physical domains. We used ordinal logistic regression models to estimate the effects of leisure activities,
APOE
ε4, and their interaction on cognitive decline, statistically adjusted for a range of potential confounders.
Results:
There were significant associations between
APOE
ε4 and faster cognitive decline, independent of potential confounders, and between leisure activities and mitigated cognitive decline. The odds ratios were 1.25 (95% CI: 1.03, 1.53) and 0.93 (95% CI: 0.89, 0.97), respectively. We found significant interactions of
APOE
ε4 with leisure activities with a
P
-value of 0.018. We also observed interactive effects of subtypes of leisure activities: participants who regularly engaged in productive activities were more likely to reduce the risk of
APOE
ε4-related cognitive decline.
Conclusion:
Our findings provide support for the indication that participating in leisure activities reduces the risk of
APOE
ε4-related cognitive decline.
The availability of timely, accessible and well documented data plays a central role in the process of digital transformation in our societies and businesses. Considering this, the European ...Commission has established an ambitious agenda that aims to leverage on the favourable technological and political context and build a society that is empowered by data-driven innovation. Within this context, geospatial data remains critically important for many businesses and public services. The process of establishing Spatial Data Infrastructures (SDIs) in response to the legal provisions of the European Union INSPIRE Directive has a long history. While INSPIRE focuses mainly on ’unlocking’ data from the public sector, there is need to address emerging technological trends, and consider the role of other actors such as the private sector and citizen science initiatives. The objective of this paper, given those bounding conditions is twofold. Firstly, we position SDI-related developments in Europe within the broader context of the current political and technological scenery. In doing so, we pay particular attention to relevant technological developments and emerging trends that we see as enablers for the evolution of European SDIs. Secondly, we propose a high level concept of a pan-European (geo)data space with a 10-year horizon in mind. We do this by considering today’s technology while trying to adopt an evolutionary approach with developments that are incremental to contemporary SDIs.
To exam the association of cognitive decline with APOE ε4 allele carriage and dietary protein intake and investigate whether there is a gene-diet (GxD) interaction of APOE ε4 allele carriage and ...dietary protein intake on cognitive decline in a nationwide cohort of older adults.
A cohort study of participants from Chinese Longitudinal Healthy Longevity Survey was conducted from 2008 to 2014. A total of 3029 participants (mean age of 77.0 years, SD = 9.0; 49.3% were women) was enrolled. We genotyped APOE ε4 allele for each participant and calculated the diversity of dietary protein intake (DDPI) by summing up the frequency of intake of the 6 protein-rich foods (meats, fish, eggs, nuts, dairy products, and bean products). We assessed cognitive function using the Mini-Mental State Examination (MMSE). We used ordinal regression model to estimate the independent and joint effects of APOE ε4 carrier and dietary protein intake on cognitive decline, adjusting for potential confounders of age, sex, education, socio-economic status, lifestyles, BMI, and cardiometabolic conditions.
There was significant association between carrying APOE ε4 allele and faster cognitive decline (Odds ratio: 1.19, 95% CI = 1.00–1.42), independent of potential confounders. While the associations of DDPI and the intake of 6 protein-rich foods with cognitive decline did not reach any statistical significance. We observed significant interactions of APOE ε4 with DDPI and fish intake, at multiple correction-adjusted Ps < 0.05. In those who were APOE ε4 carriers rather than non-carriers, both high DDPI (OR = 0.54, 95% CI: 0.34–0.88) and daily fish intake (OR = 0.43, 95% CI: 0.22–0.78) were significantly associated with slower cognitive decline, respectively. We also found that frequent intake of fish benefits women more than men regarding the mitigating of cognitive decline among APOE ε4 allele carriers (P for interaction = 0.016).
The results of this study support the hypothesis that diversified protein food intake in addition to frequent fish intake may reduce the detrimental effect of APOE ε4 on cognitive health.
Background
As new LOAD genetic risk loci are identified and more brain cell‐type specific omics data becomes available, there is an unmet need for a bioinformatics framework to prioritize genes and ...variants for testing in single‐cell molecular profiling experiments and validation using disease models and gene editing technologies. We developed a new bioinformatics pipeline to characterize and prioritize SNPs in enhancers located in LOAD‐GWAS regions based on their predicted impact to alter transcription factor (TF) binding. The proposed bioinformatics pipeline progresses from SNPs located in LOAD‐GWAS regions to a filtered set of regulatory SNPs that have a predicted strong effect on TF binding.
Method
We utilized publicly available bioinformatics software and data sources. Software: motifbreakR, UCSC Table Browser, GTEx portal and JMP. Databases: dbSNP v150, chromatin state segmentation data from the Roadmap Consortium, expression data: brain tissue from GTEX v8, monocyte from Cardiogenics, TF ChIP‐seq data from ENCODE and TF binding motifs from MotifDb.
Result
We catalogued 61 strong enhancers in LOAD‐GWAS regions that encompass 326 SNPs and 104 TF binding sites. 77 and 78 of the TFs were expressed in brain and monocytes, respectively, out of which 19 TF‐binding sites showed ChIP‐seq signals. Next, we evaluated the effect of SNPs mapped within this set of TF‐binding sites and found that 11 SNPs interrupt with the TF binding. We then determined the LD relationships between the LOAD‐risk SNP and the TF ‘interrupter’ SNP to interpret whether the LOAD association is driven by up‐ or down‐ regulation of transcription mediated by the corresponding TF. For example, a SNP within an active enhancer adjacent to PICALM disrupts the SPI1 TF binding site. The enhancer SNP and the LOAD‐GWAS SNP are in high LD, and we found that the GWAS‐risk allele links to the enhancer allele that causes loss of SPI1 binding.
Conclusion
This study provides an analytical framework to catalogue noncoding variations in enhancers located in LOAD‐GWAS loci and characterize their likelihood to perturb TF binding. The approach integrates multiple data types to characterize and prioritize SNPs for further exploration of their putative regulatory function using single‐cell multi‐omics assays and gene editing.
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