Search

In the pursuit of understanding the population of stellar remnants within the Milky Way, we analyze the sample of ∼950 microlensing events observed by the Spitzer Space Telescope between 2014 and 2019. In this study we focus on a subsample of nine microlensing events, selected based on their long timescales, small microlensing parallaxes, and joint observations by the Gaia mission, to increase the probability that the chosen lenses are massive and the mass is measurable. Among the selected events we identify lensing black holes and neutron star candidates, with potential confirmation through forthcoming release of the Gaia time-series astrometry in 2026. Utilizing Bayesian analysis and Galactic models, along with the Gaia Data Release 3 proper-motion data, four good candidates for dark remnants were identified: OGLE-2016-BLG-0293, OGLE-2018-BLG-0483, OGLE-2018-BLG-0662, and OGLE-2015-BLG-0149, with lens masses of ${3.0}_{-1.3}^{+1.8}\,{M}_{\odot }$ , ${4.7}_{-2.1}^{+3.2}\,{M}_{\odot }$ , ${3.15}_{-0.64}^{+0.66}\,{M}_{\odot }$ and ${1.40}_{-0.55}^{+0.75}\,{M}_{\odot }$ , respectively. Notably, the first two candidates are expected to exhibit astrometric microlensing signals detectable by Gaia, offering the prospect of validating the lens masses. The methodologies developed in this work will be applied to the full Spitzer microlensing sample, populating and analyzing the timescale ( t _E ) versus parallax ( π _E ) diagram to derive constraints on the population of lenses in general and massive remnants in particular.

Following Shin et al. (2023b), which is a part of the “Systematic KMTNet Planetary Anomaly Search” series (i.e., a search for planets in the 2016 KMTNet prime fields), we conduct a systematic search of the 2016 KMTNet subprime fields using a semi-machine-based algorithm to identify hidden anomalous events missed by the conventional by-eye search. We find four new planets and seven planet candidates that were buried in the KMTNet archive. The new planets are OGLE-2016-BLG-1598Lb, OGLE-2016-BLG-1800Lb, MOA-2016-BLG-526Lb, and KMT-2016-BLG-2321Lb, which show typical properties of microlensing planets, i.e., giant planets orbit M-dwarf host stars beyond their snow lines. For the planet candidates, we find planet/binary or 2L1S/1L2S degeneracies, which are an obstacle to firmly claiming planet detections. By combining the results of Shin et al. (2023b) and this work, we find a total of nine hidden planets, which is about half the number of planets discovered by eye in 2016. With this work, we have met the goal of the systematic search series for 2016, which is to build a complete microlensing planet sample. We also show that our systematic searches significantly contribute to completing the planet sample, especially for planet/host mass ratios smaller than 10 ^−3 , which were incomplete in previous by-eye searches of the KMTNet archive.

We present the analysis of the microlensing event OGLE-2014-BLG-0221, a planetary candidate event discovered in 2014. The photometric light curve is best described by a binary-lens single-source model. Our light-curve modeling finds two degenerate models, with event timescales of t _E ∼ 70 days and ∼110 days. These timescales are relatively long, indicating that the discovered system would possess a substantial mass. The two models are similar in their planetary parameters with a Jupiter mass ratio of q ∼ 10 ^−3 and a separation of s ∼ 1.1. Bayesian inference is used to estimate the physical parameters of the lens, revealing that the shorter timescale model predicts 65% and 25% probabilities of a late-type star and white dwarf host, respectively, while the longer timescale model favors a black hole host with a probability ranging from 60% to 95%, under the assumption that stars and stellar remnants have equal probabilities of hosting companions with planetary mass ratios. If the lens is a remnant, this would be the second planet found by microlensing around a stellar remnant. The current separation between the source and lens stars is 41–139 mas depending on the models. This indicates the event is now ready for high-angular-resolution follow-up observations to rule out either of the models. If precise astrometric measurements are conducted in multiple bands, the centroid shift due to the color difference between the source and lens would be detected in the luminous lens scenario.

Solar flares are broadly classified as impulsive or gradual. Ions accelerated in a gradual flare are thought to be accelerated through a shock acceleration mechanism, but the particle acceleration process in an impulsive flare is still largely unexplored. To understand the acceleration process, it is necessary to measure the high-energy gamma rays and neutrons produced by the impulsive flare. Under such circumstances, on 7 November 2004, a huge X2.0 flare occurred on the solar surface, where ions were accelerated to energies greater than 10 GeV. The accelerated primary protons collided with the solar atmosphere and produced line gamma rays and neutrons. These particles were received as neutrons and line gamma rays, respectively. Neutrons of a few GeV, on the other hand, decay to produce secondary protons while traveling 0.06 au in the solar–terrestrial space. These secondary protons arrive at the magnetopause. Although the flux of secondary protons is very low, the effect of collecting secondary protons arriving in a wide region of the magnetosphere (the Funnel or Horn effect) has resulted in significant signals being received by the solar neutron telescope at Mt. Sierra Negra (4600 m). This information suggests that ions on the solar surface are accelerated to over 10 GeV with an impulsive flare.

Abstract Macrophages play crucial roles in abdominal aortic aneurysm (AAA) formation through the inflammatory response and extracellular matrix degradation; therefore, regulating macrophages may suppress AAA formation. Interleukin‐38 (IL‐38) is a member of the IL‐1 family, which binds to IL‐36 receptor (IL1RL2) and has an anti‐inflammation effect. Because macrophages express IL1RL2, we hypothesized that IL‐38 suppresses AAA formation by controlling macrophages. We assessed a C57BL6/J mouse angiotensin II‐induced AAA model with or without IL‐38 treatment. RAW 264.7 cells were cultured with tumor necrosis factor‐α and treated with or without IL‐38. Because p38 has important roles in inflammation, we assessed p38 phosphorylation in vitro and in vivo. To clarify whether the IL‐38 effect depends on the p38 pathway, we used SB203580 to inhibit p38 phosphorylation. IL1RL2+ macrophage accumulation along with matrix metalloproteinase (MMP)‐2 and ‐9 expression was observed in mouse AAA. IL‐38 reduced the incidence of AAA formation along with reduced M1 macrophage accumulation and MMP‐2 and ‐9 expression in the AAA wall. Macrophage activities including inducible nitric oxide, MMP‐2, and MMP‐9 production and spindle‐shaped changes were significantly suppressed by IL‐38. Furthermore, we revealed that inhibition of p38 phosphorylation diminished the effects of IL‐38 on regulating macrophages to reduce AAA incidence, indicating the protective effects of IL‐38 depend on the p38 pathway. IL‐38 plays protective roles against AAA formation through regulation of macrophage accumulation in the aortic wall and modulating the inflammatory phenotype. Using IL‐38 may be a novel therapy for AAA patients.

Objective: Central venous stenosis (CVS) is a major cause of arteriovenous fistula (AVF) failure. However, central veins are relatively inaccessible to study with conventional Doppler ultrasound methods. To understand mechanisms underlying AVF failure owing to CVS, an animal model was established that creates a stenosis distal to an AVF. We hypothesized that this mouse model will show comparable morphology and physiology to human CVS. Methods: An aortocaval fistula was created between the distal aorta and inferior vena cava (IVC); a stenosis was then created distal to the fistula by partial IVC ligation. Sham-operated animals, AVF without venous stenosis, and venous stenosis without AVF were used as controls. Physiologic properties of the IVC, both upstream and downstream of the stenosis, or the corresponding sites in models without stenosis, were assessed with ultrasound examination on days 0 to 21. The spectral broadening index was measured to assess the degree of disturbed shear stress. The IVC was harvested at day 21 and specimens were analyzed with immunofluorescence. Results: The IVC diameter of mice with an AVF and stenosis showed increased upstream (P = .013), but decreased downstream diameter (P = .001) compared with mice with an AVF but without a stenosis, at all postoperative times (days 3-21). IVC wall thickness increased in mice with an AVF, compared with IVC without an AVF (upstream of stenosis: 13.9 μm vs 11.0 μm vs 4.5 μm vs 3.9 μm; P = .020; downstream of stenosis: 6.0 μm vs 6.6 μm vs μm 4.5 μm vs 3.8 μm; P = .002; AVF with stenosis, AVF, stenosis, sham, respectively). AVF patency significantly decreased in mice with an AVF and stenosis by day 21 (50% vs 90%; P = .048). The IVC of mice with AVF and stenosis showed a venous waveform with pulsatility as well as enhanced velocity at and downstream of the stenosis; similar waveforms were observed in a human case of CVS. Downstream to the stenosis, the spectral broadening index was significantly higher compared with mice with AVF alone (1.06 vs 0.78; P = .011; day 21), and there was a trend towards less immunoreactivity of both Krüppel-like factor 2 and phosphorylated-endothelial nitric oxide synthase compared with mice with an AVF alone. Conclusions: Partial IVC ligation distal to a mouse aortocaval fistula alters the fistula diameter and wall thickness, decreases patency, and increases distal disturbed flow compared with fistulae without a distal stenosis. Our mouse model of stenosis distal to an AVF may be a faithful representation of human CVS that shows similar morphology and physiology, including disturbed shear stress. : Clinical Relevance: A mouse model of venous stenosis distal to an arteriovenous fistula shows similar Doppler waveforms as those observed in a human case of central venous stenosis. These mice retain disturbed shear stress in the vein distal to the fistula, characterized by a sustained increase of the spectral broadening index and diminished expression of proteins upregulated by laminar shear stress. This novel mouse model will enable investigation of the physiology and downstream molecular pathways involved in central venous stenosis in humans.

Patients with end-stage renal failure depend on hemodialysis indefinitely without renal transplantation, requiring a long-term patent vascular access. Although an arteriovenous fistula (AVF) remains the preferred vascular access for hemodialysis because of its longer patency and fewer complications compared with other vascular accesses, the primary patency of AVF is only 50% to 60%, presenting a clinical need for improvement. AVF mature by developing a thickened vascular wall and increased diameter to adapt to arterial blood pressure and flow volume. Inflammation plays a critical role during vascular remodeling and fistula maturation; increased shear stress triggers infiltration of T cells and macrophages that initiate inflammation, with involvement of several different subsets of T cells and macrophages. We review the literature describing distinct roles of the various subsets of T cells and macrophages during vascular remodeling. Immunosuppression with sirolimus or prednisolone decreases neointimal hyperplasia during AVF maturation, suggesting novel approaches to enhance vascular remodeling. However, M2 macrophages and CD4+ T cells play essential roles during AVF maturation, suggesting that total immunosuppression may suppress adaptive vascular remodeling. Therefore, it is likely that regulation of inflammation during fistula maturation will require a balanced approach to coordinate the various inflammatory cell subsets. Advances in immunosuppressive drug development and delivery systems may allow for more targeted regulation of inflammation to improve vascular remodeling and enhance AVF maturation. (JVS–Vascular Science 2020;1:207-18.) : Clinical Relevance: Patients with end-stage renal failure depend on successful AVF maturation to have a useful access. Inflammation occurs during fistula maturation and may be a therapeutic target to improve fistula maturation and utilization. Inflammation is mainly caused by T cells and macrophages, which have several subsets with distinct phenotypes and roles during vascular remodeling. Regulation of inflammation during fistula maturation requires a balanced approach to coordinate the various inflammatory cell subsets.

Inflammation plays a part in the development of abdominal aortic aneurysm (AAA), and the gut microbiota affects host inflammation by bacterial translocation. The relationship between abdominal aortic aneurysm and the gut microbiota remains unknown. This study aimed to detect bacterial translocation in the aneurysmal wall and blood of patients with abdominal aortic aneurysm, and to investigate the effect of the gut microbiota on abdominal aortic aneurysm. We investigated 30 patients with abdominal aortic aneurysm from 2017 to 2019. We analysed the aneurysmal wall and blood using highly sensitive reverse transcription-quantitative polymerase chain reaction, and the gut microbiota was investigated using next-generation sequencing. In the 30 patients, bacteria were detected by reverse transcription- quantitative polymerase chain reaction in 19 blood samples (detection rate, 63%) and in 11 aneurysmal wall samples (detection rate, 37%). In the gut microbiota analysis, the Firmicutes/Bacteroidetes ratio was increased. The neutrophil-lymphocyte ratio was higher (2.94 ± 1.77 vs 1.96 ± 0.61, P < 0.05) and the lymphocyte-monocyte ratio was lower (4.02 ± 1.25 vs 5.86 ± 1.38, P < 0.01) in the bacterial carrier group than in the bacterial non-carrier group in blood samples. The volume of intraluminal thrombus was significantly higher in the bacterial carrier group than in the bacterial non-carrier group in aneurysmal wall samples (64.0% vs 34.7%, P < 0.05). We confirmed gut dysbiosis and bacterial translocation to the blood and aneurysmal wall in patients with abdominal aortic aneurysm. There appears to be a relationship between the gut microbiota and abdominal aortic aneurysm.

We present an analysis of microlensing event OGLE-2019-BLG-0825. This event was identified as a planetary candidate by preliminary modeling. We find that significant residuals from the best-fit static binary-lens model exist and a xallarap effect can fit the residuals very well and significantly improves χ ^2 values. On the other hand, by including the xallarap effect in our models, we find that binary-lens parameters such as mass ratio, q , and separation, s , cannot be constrained well. However, we also find that the parameters for the source system such as the orbital period and semimajor axis are consistent between all the models we analyzed. We therefore constrain the properties of the source system better than the properties of the lens system. The source system comprises a G-type main-sequence star orbited by a brown dwarf with a period of P ∼ 5 days. This analysis is the first to demonstrate that the xallarap effect does affect binary-lens parameters in planetary events. It would not be common for the presence or absence of the xallarap effect to affect lens parameters in events with long orbital periods of the source system or events with transits to caustics, but in other cases, such as this event, the xallarap effect can affect binary-lens parameters.

We report the discoveries of low-mass free-floating planet (FFP) candidates from the analysis of 2006–2014 MOA-II Galactic bulge survey data. In this data set, we found 6111 microlensing candidates and identified a statistical sample consisting of 3535 high-quality single-lens events with Einstein radius crossing times in the range 0.057 < t _E /days < 757, including 13 events that show clear finite-source effects with angular Einstein radii of 0.90 < θ _E / μ as < 332.54. Two of the 12 events with t _E < 1 day have significant finite-source effects, and one event, MOA-9y-5919, with t _E = 0.057 ± 0.016 days and θ _E = 0.90 ± 0.14 μ as, is the second terrestrial-mass FFP candidate to date. A Bayesian analysis indicates a lens mass of ${0.75}_{-0.46}^{+1.23}$ M _⊕ for this event. The low detection efficiency for short-duration events implies a large population of low-mass FFPs. The microlensing detection efficiency for low-mass planet events depends on both the Einstein radius crossing times and the angular Einstein radii, so we have used image-level simulations to determine the detection efficiency dependence on both t _E and θ _E . This allows us to use a Galactic model to simulate the t _E and θ _E distribution of events produced by the known stellar populations and models of the FFP distribution that are fit to the data. Methods like this will be needed for the more precise FFP demographics determinations from Nancy Grace Roman Space Telescope data.

We present the first measurement of the mass function of free-floating planets (FFPs), or very wide orbit planets down to an Earth mass, from the MOA-II microlensing survey in 2006–2014. Six events are likely to be due to planets with Einstein radius crossing times t _E < 0.5 days, and the shortest has t _E = 0.057 ± 0.016 days and an angular Einstein radius of θ _E = 0.90 ± 0.14 μ as. We measure the detection efficiency depending on both t _E and θ _E with image-level simulations for the first time. These short events are well modeled by a power-law mass function, ${{dN}}_{4}/d\mathrm{log}M={({2.18}_{-1.40}^{+0.52})\times (M/8\,{M}_{\oplus })}^{-{\alpha }_{4}}$ dex ^−1 star ^−1 with ${\alpha }_{4}={0.96}_{-0.27}^{+0.47}$ for M / M _⊙ < 0.02. This implies a total of $f={21}_{-13}^{+23}$ FFPs or very wide orbit planets of mass 0.33 < M / M _⊕ < 6660 per star, with a total mass of ${80}_{-47}^{+73}{M}_{\oplus }$ star ^−1 . The number of FFPs is ${19}_{-13}^{+23}$ times the number of planets in wide orbits (beyond the snow line), while the total masses are of the same order. This suggests that the FFPs have been ejected from bound planetary systems that may have had an initial mass function with a power-law index of α ∼ 0.9, which would imply a total mass of ${171}_{-52}^{+80}{M}_{\oplus }$ star ^−1 . This model predicts that Roman Space Telescope will detect ${988}_{-566}^{+1848}$ FFPs with masses down to that of Mars (including ${575}_{-424}^{+1733}$ with 0.1 ≤ M / M _⊕ ≤ 1). The Sumi et al. large Jupiter-mass FFP population is excluded.

As a part of the “Systematic KMTNet Planetary Anomaly Search” series, we report five new planets (namely, OGLE-2016-BLG-1635Lb, MOA-2016-BLG-532Lb, KMT-2016-BLG-0625Lb, OGLE-2016-BLG-1850Lb, and KMT-2016-BLG-1751Lb) and one planet candidate (KMT-2016-BLG-1855), which were found by searching 2016 KMTNet prime fields. These buried planets show a wide range of masses from Earth-class to super-Jupiter-class and are located in both the disk and the bulge. The ultimate goal of this series is to build a complete planet sample. Because our work provides a complementary sample to other planet detection methods, which have different detection sensitivities, our complete sample will help us to obtain a better understanding of planet demographics in our Galaxy.

We analyze the MOA-2020-BLG-208 gravitational microlensing event and present the discovery and characterization of a new planet, MOA-2020-BLG-208Lb, with an estimated sub-Saturn mass. With a mass ratio $q={3.17}_{-0.26}^{+0.28}\times {10}^{-4}$ , the planet lies near the peak of the mass-ratio function derived by the MOA collaboration and near the edge of expected sample sensitivity. For these estimates we provide results using two mass-law priors: one assuming that all stars have an equal planet-hosting probability, and the other assuming that planets are more likely to orbit around more massive stars. In the first scenario, we estimate that the lens system is likely to be a planet of mass ${m}_{\mathrm{planet}}={46}_{-24}^{+42}\,{M}_{\oplus }$ and a host star of mass ${M}_{\mathrm{host}}={0.43}_{-0.23}^{+0.39}\,{M}_{\odot }$ , located at a distance ${D}_{L}={7.49}_{-1.13}^{+0.99}\,\mathrm{kpc}$ . For the second scenario, we estimate ${m}_{\mathrm{planet}}={69}_{-34}^{+37}\,{M}_{\oplus }$ , ${M}_{\mathrm{host}}={0.66}_{-0.32}^{+0.35}\,{M}_{\odot }$ , and ${D}_{L}={7.81}_{-0.93}^{+0.93}\,\mathrm{kpc}$ . The planet has a projected separation as a fraction of the Einstein ring radius $s={1.3807}_{-0.0018}^{+0.0018}$ . As a cool sub-Saturn-mass planet, this planet adds to a growing collection of evidence for revised planetary formation models.

In real-time embedded systems, minimizing energy consumption is one of the most important tasks. Intra-task dynamic voltage and frequency scaling (DVFS) has been the subject of much research in the task boundary of time-constrained applications for energy reduction. The problem of optimizing energy consumption with respect to intra-task DVFS scheduling can be addressed by assigning proper operational frequencies to individual basic blocks in a program while guaranteeing the deadline. Based on the profile information of a task, we first formulate the problem in terms of integer linear programming (ILP) regarding different assumptions of transition overhead. To verify the effectiveness of ILP formulations, the most representative intra-task DVFS techniques are taken for comparisons. The results of the experiments demonstrate that the proposed ILP method achieves greater energy savings than the existing approaches. Moreover, it determines the optimal scheduling strategy in reasonable execution time for applications with a limited number of blocks.

The increasing prevalence of chronic and end-stage renal disease creates an increased need for reliable vascular access; although arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, 60% fail to mature and only 50% remain patent at 1 year. Fistulae mature by diameter expansion and wall thickening; this outward remodeling of the venous wall in the fistula environment relies on a delicate balance of extracellular matrix remodeling, inflammation, growth factor secretion, and cell adhesion molecule upregulation in the venous wall. AVF failure occurs via two distinct mechanisms with early failure secondary to lack of outward remodeling, that is, insufficient diameter expansion or wall thickening, whereas late failure occurs with excessive wall thickening due to neointimal hyperplasia and insufficient diameter expansion in a previously functional fistula. In recent years, the molecular basis of AVF maturation and failure are becoming understood to develop potential therapeutic targets to aid maturation and prevent access loss. Erythropoietin-producing hepatocellular (Eph) carcinoma receptors, along with their ligands and ephrins, determine vascular identity and are critical for vascular remodeling in the embryo. Manipulation of Eph receptor signaling in adults, as well as downstream pathways, is a potential treatment strategy to improve the rates of AVF maturation and patency. This review examines our current understanding of molecular changes occurring following fistula creation, factors predictive of fistula success, and potential areas of intervention to decrease AVF failure.

We present the analysis of three more planets from the KMTNet 2021 microlensing season. KMT-2021-BLG-0119Lb is a ∼6 M _Jup planet orbiting an early M dwarf or a K dwarf, KMT-2021-BLG-0192Lb is a ∼2 M _Nep planet orbiting an M dwarf, and KMT-2021-BLG-2294Lb is a ∼1.25 M _Nep planet orbiting a very-low-mass M dwarf or a brown dwarf. These by-eye planet detections provide an important comparison sample to the sample selected with the AnomalyFinder algorithm, and in particular, KMT-2021-BLG-2294 is a case of a planet detected by eye but not by algorithm. KMT-2021-BLG-2294Lb is part of a population of microlensing planets around very-low-mass host stars that spans the full range of planet masses, in contrast to the planet population at ≲0.1 au, which shows a strong preference for small planets.

Background Angiotensin II (Ang II) can cause hypertension and tissue impairment via AGTR1 (Ang II receptor type 1), particularly in renal proximal tubule cells, and can cause DNA damage in renal cells via nicotinamide adenine dinucleotide phosphate oxidase. BubR1 (budding uninhibited by benzimidazole‐related 1) is a multifaceted kinase that functions as a mitotic checkpoint. BubR1 expression can be induced by Ang II in smooth muscle cells in vitro, but the relationship between systemic BubR1 expression and the Ang II response is unclear. Methods and Results Twenty 24‐week‐old male BubR1 low‐expression mice (BubR1L/L mice) and age‐matched BubR1+/+ mice were used in this study. We investigated how Ang II stimulation affects BubR1L/L mice. The elevated systolic blood pressure caused by Ang II stimulation in BubR1+/+ mice was significantly attenuated in BubR1L/L mice. Additionally, an attenuated level of Ang II–induced perivascular fibrosis was observed in the kidneys of BubR1L/L mice. Immunohistochemistry revealed that the overexpression of AGTR1 induced by Ang II stimulation was repressed in BubR1L/L mice. We evaluated AGTR1 and Nox‐4 (nicotinamide adenine dinucleotide phosphate oxidase‐4) levels to determine the role of BubR1 in the Ang II response. Results from in vitro assays of renal proximal tubule cells suggest that treatment with small interfering RNA targeting BubR1 suppressed Ang II‐induced overexpression of AGTR1. Similarly, the upregulation in Nox4 and Jun N‐terminal kinase induced by Ang II administration was repressed by treatment with small interfering RNA targeting BubR1. Conclusions Ang II–induced hypertension is caused by AGTR1 overexpression in the kidneys via the upregulation of BubR1 and Nox4.

Cybersecurity is increasingly important for the safety and reliability of autonomous vehicles. The controller area network (CAN) is the most widely used in-vehicle network for automotive safety-critical applications. Enhancing the cybersecurity ability of CAN while considering the real-time, schedulability, and cost constraints becomes an urgent issue. To address this problem, a real-time, and schedulability analysis-guaranteed security mechanism [identification hopping CAN (IDH-CAN)] is proposed in this paper, which aims to improve the security performance of CAN under the constraints of automotive real-time applications. In order to support the operation of the IDH-CAN mechanism, an IDH-CAN controller is also designed and implemented on a field-programmable gate array, which can work as a hardware firewall in the data link layer of CAN to isolate cyberattacks from the physical layer. Meanwhile, to maximize the information entropy of the CAN message ID on the physical layer, the ID hopping table generation and optimization algorithms for IDH-CAN are also proposed. Then, information security evaluation experiments based on information entropy comparison are deployed. The simulation and practical evaluations demonstrate the effectiveness of the proposed mechanism in defending reverse engineering, targeted denial of service, and replay attacks without violating real-time and schedulability constraints.

Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p < 0.05; Faber score, p < 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p < 0.0001), increased fiber area (p < 0.0001), and enhanced capillary density (p < 0.01); microCT showed more arterioles (p < 0.05) and increased numbers of M2-type macrophages (p < 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p < 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p < 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.

Background Budding uninhibited by benzimidazole‐related 1 (BubR1), a cell cycle–related protein, is an essential component of the spindle checkpoint that regulates cell division. BubR1 insufficiency causes early aging‐associated vascular phenotypes. We generated low‐BubR1‐expressing mutant (BubR1L/L) and apolipoprotein E‐deficient (ApoE−/−) mice (BubR1L/L‐ApoE−/− mice) to investigate the effects of BubR1 on atherosclerosis. Methods and Results Eight‐week‐old male BubR1L/L‐ApoE−/− mice and age‐matched ApoE−/− mice were used in this study. Atherosclerotic lesion development after being fed a high‐cholesterol diet for 12 weeks was inhibited in BubR1L/L‐ApoE−/− mice compared with ApoE−/− mice, and was accompanied by decreased accumulation of macrophages. To address the relative contribution of BubR1 on bone marrow–derived cells compared with non‐bone marrow–derived cells, we performed bone marrow transplantation in ApoE−/− and BubR1L/L‐ApoE−/− mice. Decreased BubR1 in bone marrow cells and non‐bone marrow–derived cells decreased the atherosclerotic burden. In vitro assays indicated that decreased BubR1 expression impaired proliferation, but not migration, of bone marrow–derived macrophages. Conclusions BubR1 may represent a promising new target for regulating atherosclerosis.