We report the results of a systematic search for ultra-faint Milky Way satellite galaxies using data from the Dark Energy Survey (DES) and Pan-STARRS1 (PS1). Together, DES and PS1 provide multi-band ...photometry in optical/near-infrared wavelengths over ∼80% of the sky. Our search for satellite galaxies targets ∼25,000 deg2 of the high-Galactic-latitude sky reaching a 10 point-source depth of 22.5 mag in the g and r bands. While satellite galaxy searches have been performed independently on DES and PS1 before, this is the first time that a self-consistent search is performed across both data sets. We do not detect any new high-significance satellite galaxy candidates, recovering the majority of satellites previously detected in surveys of comparable depth. We characterize the sensitivity of our search using a large set of simulated satellites injected into the survey data. We use these simulations to derive both analytic and machine-learning models that accurately predict the detectability of Milky Way satellites as a function of their distance, size, luminosity, and location on the sky. To demonstrate the utility of this observational selection function, we calculate the luminosity function of Milky Way satellite galaxies, assuming that the known population of satellite galaxies is representative of the underlying distribution. We provide access to our observational selection function to facilitate comparisons with cosmological models of galaxy formation and evolution.
12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid ...mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.
Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The ...aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin (P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction (P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.
Lipid-induced insulin resistance is associated with intracellular accumulation of inhibitory intermediates depending on the prevalent fatty acid (FA) species. In cultured myotubes, ceramide and ...phosphatidic acid (PA) mediate the effects of the saturated FA palmitate and the unsaturated FA linoleate, respectively. We hypothesized that myriocin (MYR), an inhibitor of de novo ceramide synthesis, would protect against glucose intolerance in saturated fat-fed mice, while lisofylline (LSF), a functional inhibitor of PA synthesis, would protect unsaturated fat-fed mice. Mice were fed diets enriched in saturated fat, n-6 polyunsaturated fat, or chow for 6 wk. Saline, LSF (25 mg/kg · d), or MYR (0.3 mg/kg · d) were administered by mini-pumps in the final 4 wk. Glucose homeostasis was examined by glucose tolerance test. Muscle ceramide and PA were analyzed by mass spectrometry. Expression of LASS isoforms (ceramide synthases) was evaluated by immunoblotting. Both saturated and polyunsaturated fat diets increased muscle ceramide and induced glucose intolerance. MYR and LSF reduced ceramide levels in saturated and unsaturated fat-fed mice. Both inhibitors also improved glucose tolerance in unsaturated fat-fed mice, but only LSF was effective in saturated fat-fed mice. The discrepancy between ceramide and glucose tolerance suggests these improvements may not be related directly to changes in muscle ceramide and may involve other insulin-responsive tissues. Changes in the expression of LASS1 were, however, inversely correlated with alterations in glucose tolerance. The demonstration that LSF can ameliorate glucose intolerance in vivo independent of the dietary FA type indicates it may be a novel intervention for the treatment of insulin resistance.
Ceramide accumulation occurs in muscle of fat-fed mice, independent of the predominant fat source; modulation of ceramide synthase enzyme expression is associated with improved glucose tolerance by myriocin and lisofylline.
Abstract
We report the discovery of six ultra-faint Milky Way satellites identified through matched-filter searches conducted using Dark Energy Camera (DECam) data processed as part of the second ...data release of the DECam Local Volume Exploration (DELVE) survey. Leveraging deep Gemini/GMOS-N imaging (for four candidates) as well as follow-up DECam imaging (for two candidates), we characterize the morphologies and stellar populations of these systems. We find that these candidates all share faint absolute magnitudes (
M
V
≥ −3.2 mag) and old, metal-poor stellar populations (
τ
> 10 Gyr, Fe/H < −1.4 dex). Three of these systems are more extended (
r
1/2
> 15 pc), while the other three are compact (
r
1/2
< 10 pc). From these properties, we infer that the former three systems (Boötes V, Leo Minor I, and Virgo II) are consistent with ultra-faint dwarf galaxy classifications, whereas the latter three (DELVE 3, DELVE 4, and DELVE 5) are likely ultra-faint star clusters. Using data from the Gaia satellite, we confidently measure the proper motion of Boötes V, Leo Minor I, and DELVE 4, and tentatively detect a proper-motion signal from DELVE 3 and DELVE 5; no signal is detected for Virgo II. We use these measurements to explore possible associations between the newly discovered systems and the Sagittarius dwarf spheroidal, the Magellanic Clouds, and the Vast Polar Structure, finding several plausible associations. Our results offer a preview of the numerous ultra-faint stellar systems that will soon be discovered by the Vera C. Rubin Observatory and highlight the challenges of classifying the faintest stellar systems.
Abstract
The DECam Local Volume Exploration survey (DELVE) is a 126-night survey program on the 4 m Blanco Telescope at the Cerro Tololo Inter-American Observatory in Chile. DELVE seeks to understand ...the characteristics of faint satellite galaxies and other resolved stellar substructures over a range of environments in the Local Volume. DELVE will combine new DECam observations with archival DECam data to cover ∼15,000 deg
2
of high Galactic latitude (∣
b
∣ > 10°) southern sky to a 5
σ
depth of
g
,
r
,
i
,
z
∼ 23.5 mag. In addition, DELVE will cover a region of ∼2200 deg
2
around the Magellanic Clouds to a depth of
g
,
r
,
i
∼ 24.5 mag and an area of ∼135 deg
2
around four Magellanic analogs to a depth of
g
,
i
∼ 25.5 mag. Here, we present an overview of the DELVE program and progress to date. We also summarize the first DELVE public data release (DELVE DR1), which provides point-source and automatic aperture photometry for ∼520 million astronomical sources covering ∼5000 deg
2
of the southern sky to a 5
σ
point-source depth of
g
= 24.3 mag,
r
= 23.9 mag,
i
= 23.3 mag, and
z
= 22.8 mag. DELVE DR1 is publicly available via the NOIRLab Astro Data Lab science platform.
Abstract
We report results from a systematic wide-area search for faint dwarf galaxies at heliocentric distances from 0.3 to 2 Mpc using the full 6 yr of data from the Dark Energy Survey (DES). ...Unlike previous searches over the DES data, this search specifically targeted a field population of faint galaxies located beyond the Milky Way virial radius. We derive our detection efficiency for faint, resolved dwarf galaxies in the Local Volume with a set of synthetic galaxies and expect our search to be complete to
M
V
∼ (−7, −10) mag for galaxies at
D
= (0.3, 2.0) Mpc. We find no new field dwarfs in the DES footprint, but we report the discovery of one high-significance candidate dwarf galaxy at a distance of
2.2
−
0.12
+
0.05
Mpc
, a potential satellite of the Local Volume galaxy NGC 55, separated by 47′ (physical separation as small as 30 kpc). We estimate this dwarf galaxy to have an absolute
V
-band magnitude of
−
8.0
−
0.3
+
0.5
mag
and an azimuthally averaged physical half-light radius of
2.2
−
0.4
+
0.5
kpc
, making this one of the lowest surface brightness galaxies ever found with
μ
=
32.3
mag
arcsec
−
2
. This is the largest, most diffuse galaxy known at this luminosity, suggesting possible tidal interactions with its host.
We previously showed that vascular smooth muscle cells and endothelial cells cultured under high glucose conditions produced more 12(S)-hydroxyeicosatetraenoic acid (12-HETE), the 12-lipoxygenase ...(12-LO) product of arachidonate metabolism, relative to normal glucose. Because the lipoxygenase (LO) pathway has been associated with oxidant stress and the pathogenesis of atherosclerosis, we now examined 12-LO activation in vivo in a pig model of diabetes-induced accelerated atherosclerosis which displays human characteristics.
The animal model was developed in pigs who were fed a normal or high fat diet and given streptozotocin injections to produce normolipemic-normoglycaemic (NLNG), normolipemic-hyperglycaemic (NLHG), hyperlipemic-normoglycaemic (HLNG) and hyperlipemic-hyperglycaemic (HLHG) pigs. Tissue samples were obtained from key arterial beds to examine 12-LO expression at 20 weeks after the pigs began their diet.
All HG pigs maintained threefold higher serum glucose concentrations. The HL groups developed atherosclerosis but diabetic HLHG pigs showed markedly accelerated atherosclerosis (twofold) relative to non-diabetic HLNG pigs. Immunostaining showed progressive increases in 12-LO in arteries in the order NLNG, NLHG, HLNG and HLHG. Leukocyte-type 12-LO protein (immuno-blotting) as well as mRNA expression (by competitive PCR) in abdominal and coronary arteries were significantly greater in HLHG pigs than in all the other three groups. Furthermore, increased oxidant stress was observed in monocytes from NLHG and HLNG pigs, and greatly potentiated in HLHG pigs.
These results are consistent with the hypothesis that 12-LO activation plays a key role in accelerated atherosclerosis due to diabetes and hyperlipemia.
Context: Inflammation is increasingly recognized as an important contributing factor in diabetes mellitus. Lipoxygenases (LOs) produce active lipids that promote inflammatory damage by catalyzing the ...oxidation of linoleic and arachidonic acid, and LO is expressed in rodent and human islets. Little is known about the differential effect of the various hydroxyeicosatetraenoic acids (HETEs) that result from LO activity in human islets.
Objective: We compared the effects of 12-LO products on human islet viability and function.
Design: Human islets were treated with stable compounds derived from LOs: 12(S)-HETE, 15HETE, 12HPETE, and 12RHETE and then examined for insulin secretion and islet viability. The p38-MAPK (p38) and JNK stress-activated pathways were investigated as mechanisms of 12-LO-mediated islet inhibition in rodent and human islets.
Results: Insulin secretion was consistently reduced by 12(S)-HETE and 12HPETE. 12(S)-HETE at 1 nm reduced viability activity by 32% measured by MTT assay and increased cell death by 50% at 100 nm in human islets. These effects were partially reversed with lisofylline, a small-molecule antiinflammatory compound that protects mitochondrial function. 12(S)-HETE increased phosphorylated p38-MAPK (pp38) protein activity in human islets. Injecting 12-LO siRNA into C57BL/6 mice reduced 12-LO and pp38-MAPK protein levels in mouse islets. The addition of proinflammatory cytokines increased pp38 levels in normal mouse islets but not in siRNA-treated islets.
Conclusions: These data suggest that 12(S)-HETE reduces insulin secretion and increases cell death in human islets. The 12-LO pathway is present in human islets, and expression is up-regulated by inflammatory cytokines. Reduction of 12-LO activity could thus provide a new therapeutic approach to protect human β-cells from inflammatory injury.
12-Lipoxygenase is an important inflammatory pathway leading to damage of human islets.
Inflammation is emerging as an important mechanism for micro- and macrovascular complication of diabetes. The macrophage plays a key role in the chronic inflammatory response in part by generating ...particular cytokines. IL-1β, IL-6, IL12, IL-18, TNFα, and interferon-γ are produced primarily in macrophages and have been associated with accelerated atherosclerosis and altered vascular wall function. In this study, we evaluated the effect and mechanism of high glucose (HG) on gene expression of these cytokines in mouse peritoneal macrophages (MPM). HG led to a 2-fold increase in the mRNA expression of these cytokines, with IL-12 showing the highest activation (5.4-fold) in a time-dependent (3–12 h) and dose-dependent (10, 17.5, and 25 mmol/liter) manner. The effects were specific to HG because mannitol and 3-O-methyl-glucose had no effect on cytokine mRNA expression. HG also increased IL-12 protein accumulation from MPM. We also explored the role of induced and spontaneous diabetes on inflammatory cytokine expression in MPM. Increases in expression in MPM of multiple inflammatory cytokines, including a 20-fold increase in IL-12 mRNA, were observed in streptozotocin-induced type 1 diabetic mice as well as type 2 diabetic db/db mice, suggesting that cytokine gene expression is increased by hyperglycemia in vivo. We next explored potential mechanisms of HG-induced increases in IL-12 mRNA. HG increased the activity of protein kinase C, p38 MAPK (p38), c-Jun terminal kinase, and inhibitory-κB kinase in MPM. Furthermore, inhibitors of these signaling pathways significantly reduced HG-induced IL-12 mRNA expression in MPM. These results provide evidence for a potentially important mechanism linking elevated glucose and diabetes to inflammation.
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