Age-related changes in bile acid synthesis and hepatic nuclear receptor expression

BACKGROUND:Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7alpha-hydroxylase and related nuclear receptor expression in human livers.DESIGN:Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7alpha-hydroxylase and related nuclear receptors and co-activators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, were assayed by gas-liquid chromatography:mass spectrometry.RESULTS:Ageing was inversely correlated with serum 7alpha-hydroxy-4-cholesten-3-one and with cholesterol 7alpha-hydroxylase mRNA levels (r = -0.44 and r = -0.45 on a semi-log scale, respectively, P < 0.05). Among different nuclear factors, cholesterol 7alpha-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0.55 on a log scale, P < 0.05); hepatocyte nuclear factor-4 levels were also inversely correlated with age (r = -0.64 on a semi-log scale, P < 0.05). Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7alpha-hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7alpha-hydroxylase was observed.CONCLUSIONS:Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor-4 and consequently of cholesterol 7alpha-hydroxylase. Age-related modifications of the growth hormone/insulin-like growth factor axis might play a role. These findings may help to elucidate the pathophysiology of age-related modifications of cholesterol metabolism

Physical Exercise Affects Adipose Tissue Profile and Prevents Arterial Thrombosis in BDNF Val66Met Mice

Adipose tissue accumulation is an independent and modifiable risk factor for cardiovascular disease (CVD). The recent CVD European Guidelines strongly recommend regular physical exercise (PE) as a management strategy for prevention and treatment of CVD associated with metabolic disorders and obesity. Although mutations as well as common genetic variants, including the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, are associated with increased body weight, eating and neuropsychiatric disorders, and myocardial infarction, the effect of this polymorphism on adipose tissue accumulation and regulation as well as its relation to obesity/thrombosis remains to be elucidated. Here, we showed that white adipose tissue (WAT) of humanized knock-in BDNFVal66Met (BDNFMet/Met) mice is characterized by an altered morphology and an enhanced inflammatory profile compared to wild-type BDNFVal/Val. Four weeks of voluntary PE restored the adipocyte size distribution, counteracted the inflammatory profile of adipose tissue, and prevented the prothrombotic phenotype displayed, per se, by BDNFMet/Met mice. C3H10T1/2 cells treated with the Pro-BDNFMet peptide well recapitulated the gene alterations observed in BDNFMet/Met WAT mice. In conclusion, these data indicate the strong impact of lifestyle, in particular of the beneficial effect of PE, on the management of arterial thrombosis and inflammation associated with obesity in relation to the specific BDNF Val66Met mutation

Cross-Sectional Associations between Exposure to Persistent Organic Pollutants and Leukocyte Telomere Length among U.S. Adults in NHANES, 2001-2002.

Background: Exposure to persistent organic pollutants (POPs) such as dioxins, furans, and polychlorinated biphenyls (PCBs) may influence leukocyte telomere length (LTL), a biomarker associated with chronic disease. In vitro research suggests dioxins may bind to the aryl hydrocarbon receptor (AhR) and induce telomerase activity, which elongates LTL. However, few epidemiologic studies have investigated associations between POPs and LTL. Objectives: We examined the association between 18 PCBs, 7 dioxins, and 9 furans and LTL among 1,330 U.S. adults from NHANES 2001-2002. Methods: We created three summed POP metrics based on toxic equivalency factor (TEF), a potency measure including affinity for the AhR: (a) non-dioxin-like PCBs (composed of 10 non-dioxin-like PCBs; no AhR affinity and no TEF); (b) non-ortho PCBs (composed of 2 non-ortho-substituted PCBs with high TEFs); and (c) toxic equivalency (TEQ) (composed of 7 dioxins, 9 furans, 2 non-ortho-substituted PCBs, and 6 mono-ortho-substituted PCBs; weighted by TEF). We tested the association between each metric and LTL using linear regression, adjusting for demographics, blood cell count and distribution, and another metric with a different TEF (i.e., non-ortho PCBs and TEQ adjusted for non-dioxin-like PCBs; non-dioxin-like PCBs adjusted for non-ortho PCBs). Results: In adjusted models, each doubling of serum concentrations of non-ortho PCBs and TEQ was associated with 3.74% (95% CI: 2.10, 5.40) and 5.29% (95% CI: 1.66, 9.05) longer LTLs, respectively. Compared with the lowest quartile, the highest quartile of exposure was associated with 9.16% (95% CI: 2.96, 15.73) and 7.84% (95% CI: -0.53, 16.92) longer LTLs, respectively. Non-dioxin-like PCBs were not associated with LTL. Conclusions: POPs with high TEFs and AhR affinity were associated with longer LTL. Because many dioxin-associated cancers are also associated with longer LTL, these results may provide insight into the mechanisms underlying PCB- and dioxin-related carcinogenesis

Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals.

Low-grade systemic inflammation associated to obesity leads to cardiovascular complications, caused partly by infiltration of adipose and vascular tissue by effector T cells. The signals leading to T cell differentiation and tissue infiltration during obesity are poorly understood. We tested whether saturated fatty acid-induced metabolic stress affects differentiation and trafficking patterns of CD4+ T cells. Memory CD4+ T cells primed in high-fat diet-fed donors preferentially migrated to non-lymphoid, inflammatory sites, independent of the metabolic status of the hosts. This was due to biased CD4+ T cell differentiation into CD44hi-CCR7lo-CD62Llo-CXCR3+-LFA1+ effector memory-like T cells upon priming in high-fat diet-fed animals. Similar phenotype was observed in obese subjects in a cohort of free-living people. This developmental bias was independent of any crosstalk between CD4+ T cells and dendritic cells and was mediated via direct exposure of CD4+ T cells to palmitate, leading to increased activation of a PI3K p110δ-Akt-dependent pathway upon priming

The ATP-binding cassette transporter A1 regulates phosphoantigen release and V&#206;&#179;39V&#206;&#180;2 T cell activation by dendritic cells

V\uce\ub339V\uce\ub42 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce V\uce\ub339V\uce\ub42 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXR\uce\ub1 nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune V\uce\ub339V\uce\ub42 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation

TROPOMI tropospheric ozone column data: geophysical assessment and comparison to ozonesondes, GOME-2B and OMI

Ozone in the troposphere affects humans and ecosystems as a pollutant and as a greenhouse gas. Observing, understanding and modelling this dual role, as well as monitoring effects of international regulations on air quality and climate change, however, challenge measurement systems to operate at opposite ends of the spatio-temporal scale ladder. Aboard the ESA/EU Copernicus Sentinel-5 Precursor (S5P) satellite launched in October 2017, the TROPOspheric Monitoring Instrument (TROPOMI) aspires to take the next leap forward by measuring ozone and its precursors at unprecedented horizontal resolution until at least the mid-2020s. In this work, we assess the quality of TROPOMI's first release (V01.01.05–08) of tropical tropospheric ozone column (TrOC) data. Derived with the convective cloud differential (CCD) method, TROPOMI daily TrOC data represent the 3 d moving mean ozone column between the surface and 270 hPa under clear-sky conditions gridded at 0.5∘ latitude by 1∘ longitude resolution. Comparisons to almost 2 years of co-located SHADOZ ozonesonde and satellite data (Aura OMI and MetOp-B GOME-2) conclude to TROPOMI biases between −0.1 and +2.3 DU (<+13 %) when averaged over the tropical belt. The field of the bias is essentially uniform in space (deviations <1 DU) and stable in time at the 1.5–2.5 DU level. However, the record is still fairly short, and continued monitoring will be key to clarify whether observed patterns and stability persist, alter behaviour or disappear. Biases are partially due to TROPOMI and the reference data records themselves, but they can also be linked to systematic effects of the non-perfect co-locations. Random uncertainty due to co-location mismatch contributes considerably to the 2.6–4.6 DU (∼14 %–23 %) statistical dispersion observed in the difference time series. We circumvent part of this problem by employing the triple co-location analysis technique and infer that TROPOMI single-measurement precision is better than 1.5–2.5 DU (∼8 %–13 %), in line with uncertainty estimates reported in the data files. Hence, the TROPOMI precision is judged to be 20 %–25 % better than for its predecessors OMI and GOME-2B, while sampling at 4 times better spatial resolution and almost 2 times better temporal resolution. Using TROPOMI tropospheric ozone columns at maximal resolution nevertheless requires consideration of correlated errors at small scales of up to 5 DU due to the inevitable interplay of satellite orbit and cloud coverage. Two particular types of sampling error are investigated, and we suggest how these can be identified or remedied. Our study confirms that major known geophysical patterns and signals of the tropical tropospheric ozone field are imprinted in TROPOMI's 2-year data record. These include the permanent zonal wave-one pattern, the pervasive annual and semiannual cycles, the high levels of ozone due to biomass burning around the Atlantic basin, and enhanced convective activity cycles associated with the Madden–Julian Oscillation over the Indo-Pacific warm pool. TROPOMI's combination of higher precision and higher resolution reveals details of these patterns and the processes involved, at considerably smaller spatial and temporal scales and with more complete coverage than contemporary satellite sounders. If the accuracy of future TROPOMI data proves to remain stable with time, these hold great potential to be included in Climate Data Records, as well as serve as a travelling standard to interconnect the upcoming constellation of air quality satellites in geostationary and low Earth orbits

Use of an implantable loop recorder to increase the diagnostic yield in unexplained syncope: results from the PICTURE registry

To collect information on the use of the Reveal implantable loop recorder (ILR) in the patient care pathway and to investigate its effectiveness in the diagnosis of unexplained recurrent syncope in everyday clinical practice

Gene Set Enrichment in eQTL Data Identifies Novel Annotations and Pathway Regulators

Genome-wide gene expression profiling has been extensively used to generate biological hypotheses based on differential expression. Recently, many studies have used microarrays to measure gene expression levels across genetic mapping populations. These gene expression phenotypes have been used for genome-wide association analyses, an analysis referred to as expression QTL (eQTL) mapping. Here, eQTL analysis was performed in adipose tissue from 28 inbred strains of mice. We focused our analysis on “trans-eQTL bands”, defined as instances in which the expression patterns of many genes were all associated to a common genetic locus. Genes comprising trans-eQTL bands were screened for enrichments in functional gene sets representing known biological pathways, and genes located at associated trans-eQTL band loci were considered candidate transcriptional modulators. We demonstrate that these patterns were enriched for previously characterized relationships between known upstream transcriptional regulators and their downstream target genes. Moreover, we used this strategy to identify both novel regulators and novel members of known pathways. Finally, based on a putative regulatory relationship identified in our analysis, we identified and validated a previously uncharacterized role for cyclin H in the regulation of oxidative phosphorylation. We believe that the specific molecular hypotheses generated in this study will reveal many additional pathway members and regulators, and that the analysis approaches described herein will be broadly applicable to other eQTL data sets

Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naive animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems

Mercury dynamics in a San Francisco estuary tidal wetland : assessing dynamics using in situ measurements

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Estuaries and Coasts 35 (2012): 1036-1048, doi:10.1007/s12237-012-9501-3.We used high-resolution in situ measurements of turbidity and fluorescent dissolved organic matter (FDOM) to quantitatively estimate the tidally driven exchange of mercury (Hg) between the waters of the San Francisco estuary and Browns Island, a tidal wetland. Turbidity and FDOM—representative of particle-associated and filter-passing Hg, respectively—together predicted 94 % of the observed variability in measured total mercury concentration in unfiltered water samples (UTHg) collected during a single tidal cycle in spring, fall, and winter, 2005–2006. Continuous in situ turbidity and FDOM data spanning at least a full spring-neap period were used to generate UTHg concentration time series using this relationship, and then combined with water discharge measurements to calculate Hg fluxes in each season. Wetlands are generally considered to be sinks for sediment and associated mercury. However, during the three periods of monitoring, Browns Island wetland did not appreciably accumulate Hg. Instead, gradual tidally driven export of UTHg from the wetland offset the large episodic on-island fluxes associated with high wind events. Exports were highest during large spring tides, when ebbing waters relatively enriched in FDOM, dissolved organic carbon (DOC), and filter-passing mercury drained from the marsh into the open waters of the estuary. On-island flux of UTHg, which was largely particle-associated, was highest during strong winds coincident with flood tides. Our results demonstrate that processes driving UTHg fluxes in tidal wetlands encompass both the dissolved and particulate phases and multiple timescales, necessitating longer term monitoring to adequately quantify fluxes.This work was supported by funding from the California Bay Delta Authority Ecosystem Restoration and Drinking Water Programs (grant ERP-00- G01) and matching funds from the United States Geological Survey Cooperative Research Program