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"Fowler, Joseph"
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Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice
Blood vessels are continually exposed to circulating lipids, and elevation of ApoB-containing lipoproteins causes atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelial-dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state.
Journal Article
Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes; however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. Here, we studied the role of cholesterol and a key transcription regulator of cholesterol homeostasis, SREBP2, in the EC responses to inflammatory stress. Treatment of primary human ECs with pro-inflammatory cytokines upregulated SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-κB DNA binding and canonical SCAP-SREBP2 processing. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Detailed analysis of NF-κB inducible genes that may impact sterol sensing resulted in the identification of a novel RELA -inducible target, STARD10 , that mediates accessible cholesterol homeostasis in ECs. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC.
Journal Article
Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells
In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in
Ldlr-
KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL.
Atherosclerosis is caused by low-density lipoprotein (LDL) buildup in the vessel wall, a process thought to be mediated by LDL receptor alone. Here, the authors show that the endothelium can uptake LDL via ALK1, a TGFβ signalling receptor, suggesting new therapies for blocking LDL accumulation in the vessel wall.
Journal Article
Rosacea and risk of cancer in Denmark
•Rosacea is an inflammatory facial skin disorder with a prevalence of 5% in Denmark.•Studies on cancer risk in rosacea are lacking.•We found an increased risk non-melanoma skin cancer, breast cancer, and hepatic cancer, and a reduced risk of lung in patients with rosacea.
Rosacea is a common facial skin disorder with an estimated prevalence of 5–10% among Caucasians.
We compared cancer incidence in patients previously diagnosed with rosacea with that in the general population.
Nationwide cohort study of the Danish population using individual-level linkage of administrative registers. All Danish citizens aged ≥18years were followed from January 1st 2008 to December 31st 2012. Patients with rosacea (the exposure) were compared with the general population, serving as control subjects. The outcome was a diagnosis of one of the following cancers: breast, ovarian, endometrial, cervical, kidney, malignant melanoma, non-melanoma skin cancer (NMSC), pancreatic, hepatic, thyroid, esophageal, and lung cancer. Baseline prevalence of cancers were assessed, incidence rates per 1000 person-years were calculated, and hazard ratios (HRs) adjusted for age, sex, socio-economic status, and healthcare consumption were estimated by Cox regression models.
The study comprised a total of 49,475 patients with rosacea and 4,312,213 subjects from the general population. There was no increased risk of malignant melanoma, ovarian, endometrial, cervical, esophageal, kidney, pancreatic, or thyroid cancer. However the risk of hepatic cancer (HR 1.42; 95% confidence interval [CI] 1.06–1.90), NMSC (HR 95% CI 1.36; 1.26–1.47), and breast cancer (HR 1.25; 95% CI 1.15–1.36) was significantly increased, and the risk of incident lung cancer was significantly decreased (HR 0.78; 95% CI 0.69–0.89).
We found an increased risk of NMSC, breast cancer, and hepatic cancer, and a reduced risk of lung cancer, among patients with rosacea. These results are in contrast to the limited published data on cancers in rosacea, and further studies are warranted to elucidate the potential relationship between rosacea and various cancers. The findings add to the overall clinical description of patients with rosacea.
Journal Article
Nationwide Assessment of Cause-Specific Mortality in Patients with Rosacea: A Cohort Study in Denmark
Background
Emerging data suggest that rosacea is associated with several comorbidities; however, the causes of mortality in patients with rosacea have not yet been investigated.
Objective
We evaluated all-cause and cause-specific death rates in patients with rosacea in a population-based Danish cohort study.
Methods
All Danish individuals aged ≥18 years between 1 January 1997 and 31 December 2012 with rosacea diagnosed by hospital dermatologists were linked in nationwide registers and compared with age- and sex-matched general-population subjects (1:5 ratio). Death rates were calculated per 1000 person-years, and hazard ratios (HRs) were estimated using Cox regression models.
Results
The total cohort (
n
= 35,958) included 5993 patients with rosacea and 29,965 age- and sex-matched individuals from the general population. During the maximum 15 years of follow-up, 664 (11.1 %) patients with rosacea and 3121 (10.4 %) patients in the reference population died. The risk of all-cause mortality was similar in patients with rosacea and the reference population [HR 1.06, 95 % confidence interval (CI) 0.98–1.15]. Analyses of cause-specific mortality revealed a significantly increased risk of death due to gastrointestinal diseases in patients with rosacea (HR 1.95, 95 % CI 1.31–2.89), primarily related to hepatic disease. No increased risk of death due to other major disease categories, e.g. cancer, cardiovascular, neurological, or infectious diseases was observed.
Conclusion
We observed a significantly increased risk of death due to gastrointestinal diseases (primarily hepatic disease) in patients with rosacea; however, we found no increased risk of death due to other causes such as cardiovascular or neurological diseases. Although this does not necessarily imply a causal link, the findings underscore the association between rosacea and gastrointestinal disease, but also that rosacea may be associated with increased risk factors, including alcohol consumption.
Journal Article
Ultrafast Time-Resolved Hard X-Ray Emission Spectroscopy on a Tabletop
Experimental tools capable of monitoring both atomic and electronic structure on ultrafast (femtosecond to picosecond) time scales are needed for investigating photophysical processes fundamental to light harvesting, photocatalysis, energy and data storage, and optical display technologies. Time-resolved hard x-ray (>3keV ) spectroscopies have proven valuable for these measurements due to their elemental specificity and sensitivity to geometric and electronic structures. Here, we present the first tabletop apparatus capable of performing time-resolved x-ray emission spectroscopy. The time resolution of the apparatus is better than 6 ps. By combining a compact laser-driven plasma source with a highly efficient array of microcalorimeter x-ray detectors, we are able to observe photoinduced spin changes in an archetypal polypyridyl iron complex [Fe(2,2′−bipyridine)3]2+ and accurately measure the lifetime of the quintet spin state. Our results demonstrate that ultrafast hard x-ray emission spectroscopy is no longer confined to large facilities and now can be performed in conventional laboratories with 10 times better time resolution than at synchrotrons. Our results are enabled, in part, by a 100- to 1000-fold increase in x-ray collection efficiency compared to current techniques.
Journal Article
Prevalence and trend of allergen sensitization in patients with a diagnosis of stasis dermatitis referred for patch testing, North American contact dermatitis group data, 2001–2016
Background
Few studies explored the relationship between stasis dermatitis (SD) and allergic contact dermatitis (ACD).
Objective
To examine trends, associations, and clinical relevance of ACD in patients referred for patch testing who had a final SD diagnosis.
Methods
Retrospective analysis from 2001 to 2016 of 38,723 patients from the North American Contact Dermatitis Group.
Results
After patch testing, 303 (0.7%) patients were diagnosed with SD; 46.7% had a concomitant diagnosis of ACD. Patients with vs. without a final SD diagnosis had similar proportions of ≥ 1 positive allergic reaction (59.7% vs. 64.7%; Chi-square,
P
= 0.0724) but higher odds of allergic reactions to fragrance mix I, bacitracin, quaternium-15,
Myroxylon pereirae
, benzalkonium chloride, ethyleneurea melamine formaldehyde, diazolidinyl urea, and propylene glycol. The most commonly relevant allergens in patients with final SD diagnosis were fragrance mix I,
Myroxylon pereirae
, bacitracin, quaternium-15, and formaldehyde. The most common allergen sources were personal care products, topical medications and other health aid products.
Conclusion
Nearly half of patients with a final SD diagnosis were also diagnosed with ACD, supporting the role of patch testing in select SD patients.
Journal Article
A tabletop X-ray tomography instrument for nanometer-scale imaging: reconstructions
We show three-dimensional reconstructions of a region of an integrated circuit from a 130 nm copper process. The reconstructions employ x-ray computed tomography, measured with a new and innovative high-magnification x-ray microscope. The instrument uses a focused electron beam to generate x-rays in a 100 nm spot and energy-resolving x-ray detectors that minimize backgrounds and hold promise for the identification of materials within the sample. The x-ray generation target, a layer of platinum, is fabricated on the circuit wafer itself. A region of interest is imaged from a limited range of angles and without physically removing the region from the larger circuit. The reconstruction is consistent with the circuit’s design file.
Journal Article
Kinetic inductance current sensor for visible to near-infrared wavelength transition-edge sensor readout
Single-photon detectors based on the superconducting transition-edge sensor are used in a number of visible to near-infrared applications, particularly for photon-number-resolving measurements in quantum information science. To be practical for large-scale spectroscopic imaging or photonic quantum computing applications, the size of visible to near-infrared transition-edge sensor arrays and their associated readouts must be increased from a few pixels to many thousands. In this manuscript, we introduce the kinetic inductance current sensor, a scalable readout technology that exploits the nonlinear kinetic inductance in a superconducting resonator to make sensitive current measurements. Kinetic inductance current sensors can replace superconducting quantum interference devices for many applications because of their ability to measure fast, high slew-rate signals, their compatibility with standard microwave frequency-division multiplexing techniques, and their relatively simple fabrication. Here, we demonstrate the readout of a visible to near-infrared transition-edge sensor using a kinetic inductance current sensor with 3.7 MHz of bandwidth. We measure a readout noise of
1.4
pA
/
Hz
, considerably below the detector noise at frequencies of interest, and an energy resolution of (0.137 ± 0.001) eV at 0.8 eV, comparable to resolutions observed with non-multiplexed superconducting quantum interference device readouts.
Paul Szypryt and co-authors present a kinetic inductance current sensor which uses nonlinear kinetic inductance in a superconducting resonator for current measurement. Their device demonstrates a readout noise below the level of a coupled transition-edge sensor.
Journal Article