| 1. |
- Benson, Tyler W., et al.
(författare)
-
Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms
- 2023
-
Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 147:14, s. 1079-1096
-
Tidskriftsartikel (refereegranskat)abstract
- Background:Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.Methods:TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3(-/-)). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA.Results:Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3(-/-) mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK.Conclusions:These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.
|
|
| 2. |
- Benson, Tyler W, et al.
(författare)
-
Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.
- 2023
-
Ingår i: bioRxiv : the preprint server for biology.
-
Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.
|
|
| 3. |
- Bellm, Eric C., et al.
(författare)
-
An Optically Discovered Outburst from XTE J1859+226
- 2023
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 956:1
-
Tidskriftsartikel (refereegranskat)abstract
- Using the Zwicky Transient Facility, in 2021 February we identified the first known outburst of the black hole X-ray transient XTE J1859+226 since its discovery in 1999. The outburst was visible at X-ray, UV, and optical wavelengths for less than 20 days, substantially shorter than its full outburst of 320 days in 1999, and the observed peak luminosity was 2 orders of magnitude lower. Its peak bolometric luminosity was only 2 × 1035 erg s−1, implying an Eddington fraction of about 3 × 10−4. The source remained in the hard spectral state throughout the outburst. From optical spectroscopy measurements we estimate an outer disk radius of 1011 cm. The low observed X-ray luminosity is not sufficient to irradiate the entire disk, but we observe a surprising exponential decline in the X-ray light curve. These observations highlight the potential of optical and infrared synoptic surveys to discover low-luminosity activity from X-ray transients.
|
|
| 4. |
- Coughlin, Michael W., et al.
(författare)
-
A Data Science Platform to Enable Time-domain Astronomy
- 2023
-
Ingår i: Astrophysical Journal Supplement Series. - 0067-0049 .- 1538-4365. ; 267:2
-
Tidskriftsartikel (refereegranskat)abstract
- SkyPortal is an open-source software package designed to discover interesting transients efficiently, manage follow-up, perform characterization, and visualize the results. By enabling fast access to archival and catalog data, crossmatching heterogeneous data streams, and the triggering and monitoring of on-demand observations for further characterization, a SkyPortal-based platform has been operating at scale for >2 yr for the Zwicky Transient Facility Phase II community, with hundreds of users, containing tens of millions of time-domain sources, interacting with dozens of telescopes, and enabling community reporting. While SkyPortal emphasizes rich user experiences across common front-end workflows, recognizing that scientific inquiry is increasingly performed programmatically, SkyPortal also surfaces an extensive and well-documented application programming interface system. From back-end and front-end software to data science analysis tools and visualization frameworks, the SkyPortal design emphasizes the reuse and leveraging of best-in-class approaches, with a strong extensibility ethos. For instance, SkyPortal now leverages ChatGPT large language models to generate and surface source-level human-readable summaries automatically. With the imminent restart of the next generation of gravitational-wave detectors, SkyPortal now also includes dedicated multimessenger features addressing the requirements of rapid multimessenger follow-up: multitelescope management, team/group organizing interfaces, and crossmatching of multimessenger data streams with time-domain optical surveys, with interfaces sufficiently intuitive for newcomers to the field. This paper focuses on the detailed implementations, capabilities, and early science results that establish SkyPortal as a community software package ready to take on the data science challenges and opportunities presented by this next chapter in the multimessenger era.
|
|
| 5. |
- Pang, Peter T. H., et al.
(författare)
-
An updated nuclear-physics and multi-messenger astrophysics framework for binary neutron star mergers
- 2023
-
Ingår i: Nature Communications. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- The multi-messenger detection of the gravitational-wave signal GW170817, the corresponding kilonova AT2017gfo and the short gamma-ray burst GRB170817A, as well as the observed afterglow has delivered a scientific breakthrough. For an accurate interpretation of all these different messengers, one requires robust theoretical models that describe the emitted gravitational-wave, the electromagnetic emission, and dense matter reliably. In addition, one needs efficient and accurate computational tools to ensure a correct cross-correlation between the models and the observational data. For this purpose, we have developed the Nuclear-physics and Multi-Messenger Astrophysics framework NMMA. The code allows incorporation of nuclear-physics constraints at low densities as well as X-ray and radio observations of isolated neutron stars. In previous works, the NMMA code has allowed us to constrain the equation of state of supranuclear dense matter, to measure the Hubble constant, and to compare dense-matter physics probed in neutron-star mergers and in heavy-ion collisions, and to classify electromagnetic observations and perform model selection. Here, we show an extension of the NMMA code as a first attempt of analyzing the gravitational-wave signal, the kilonova, and the gamma-ray burst afterglow simultaneously. Incorporating all available information, we estimate the radius of a 1.4M⊙ neutron star to be R = 11.98+0.35−0.40 km.
|
|
| 6. |
- Srinivasaragavan, Gokul P., et al.
(författare)
-
A Sensitive Search for Supernova Emission Associated with the Extremely Energetic and Nearby GRB 221009A
- 2023
-
Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 949:2
-
Tidskriftsartikel (refereegranskat)abstract
- We report observations of the optical counterpart of the long gamma-ray burst GRB 221009A. Due to the extreme rarity of being both nearby (z = 0.151) and highly energetic (E ( gamma,iso) >= 10(54) erg), GRB 221009A offers a unique opportunity to probe the connection between massive star core collapse and relativistic jet formation across a very broad range of gamma-ray properties. Adopting a phenomenological power-law model for the afterglow and host galaxy estimates from high-resolution Hubble Space Telescope imaging, we use Bayesian model comparison techniques to determine the likelihood of an associated supernova (SN) contributing excess flux to the optical light curve. Though not conclusive, we find moderate evidence (K (Bayes) = 10(1.2)) for the presence of an additional component arising from an associated SN, SN 2022xiw, and find that it must be substantially fainter (<67% as bright at the 99% confidence interval) than SN 1998bw. Given the large and uncertain line-of-sight extinction, we attempt to constrain the SN parameters (M (Ni), M (ej), and E (KE)) under several different assumptions with respect to the host galaxy's extinction. We find properties that are broadly consistent with previous GRB-associated SNe: M (Ni) = 0.05-0.25 M (circle dot), M (ej) = 3.5-11.1 M (circle dot), and E (KE) = (1.6-5.2) x 10(52) erg. We note that these properties are weakly constrained due to the faintness of the SN with respect to the afterglow and host emission, but we do find a robust upper limit on M (Ni) of M (Ni) < 0.36 M (circle dot). Given the tremendous range in isotropic gamma-ray energy release exhibited by GRBs (seven orders of magnitude), the SN emission appears to be decoupled from the central engine in these systems.
|
|
