A. J. Connolly

Stanford Medicine, Stanford, California, United States

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Publications (304)1037.05 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocte (ESC-CM) transplantation, thereby potentially preventing dilative remodelling and progression to heart failure. Assessment of transport stability, long term survival, structural organisation, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction (MI) model. We constructed EHMs from ESC-CMs and released them for transatlantic shipping following predefined quality control criteria. Two days of shipment did not lead to adverse effects on cell viability or contractile performance of EHMs (n=3, P=0.83, P=0.87). After ischemia / reperfusion (I/R) injury, EHMs were implanted onto immunocompromised rat hearts at 1 month to simulate chronic ischemia. Bioluminescence imaging (BLI) showed stable engraftment with no significant cell loss between week 2 and 12 (n=6, P=0.67), preserving up to 25% of the transplanted cells. Despite high engraftment rates and attenuated disease progression (change in ejection fraction for EHMs -6.7±1.4% vs control -10.9±1.5%, n>12, P=0.05), we observed no difference between EHMs containing viable or non-viable human cardiomyocytes in this chronic xenotransplantation model (n>12, P=0.41). Grafted cardiomyocytes showed enhanced sarcomere alignment and increased connexin 43 expression at 220 days after transplantation. No teratomas or tumors were found in any of the animals (n=14) used for long-term monitoring. EHM transplantation led to high engraftment rates, long term survival, and progressive maturation of human cardiomyocytes. However, cell engraftment was not correlated with functional improvements in this chronic MI model. Most importantly, the safety of this approach was demonstrated by the lack of tumor or teratoma formation.
    Circulation Research 08/2015; DOI:10.1161/CIRCRESAHA.115.306985 · 11.02 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by progressive elevation of the pulmonary pressures that, in the absence of therapy, results in chronic right-heart failure and premature death. The vascular pathology of PAH is characterized by progressive loss of small (diameter, less than 50 μm) peripheral pulmonary arteries along with abnormal medial thickening, neointimal formation, and intraluminal narrowing of the remaining pulmonary arteries. Vascular pathology correlates with disease severity, given that hemodynamic effects and disease outcomes are worse in patients with advanced compared with lower-grade lesions. Novel imaging tools are urgently needed that demonstrate the extent of vascular remodeling in PAH patients during diagnosis and treatment monitoring. Optical coherence tomography (OCT) is a catheter-based intravascular imaging technique used to obtain high-resolution 2D and 3D cross-sectional images of coronary arteries, thus revealing the extent of vascular wall pathology due to diseases such as atherosclerosis and in-stent restenosis; its utility as a diagnostic tool in the assessment of the pulmonary circulation is unknown. Here we show that OCT provides high-definition images that capture the morphology of pulmonary arterial walls in explanted human lungs and during pulmonary arterial catheterization of an adult pig. We conclude that OCT may facilitate the evaluation of patients with PAH by disclosing the degree of wall remodeling present in pulmonary vessels. Future studies are warranted to determine whether this information complements the hemodynamic and functional assessments routinely performed in PAH patients, facilitates treatment selection, and improves estimates of prognosis and outcome.
    Comparative medicine 07/2015; 65(3):217-24. · 0.74 Impact Factor
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    ABSTRACT: Many scientific data-intensive applications perform iterative computations on array data. There exist multiple engines specialized for array processing. These engines efficiently support various types of operations, but none includes native support for iterative processing. In this paper, we develop a model for iterative array computations and a series of optimizations. We evaluate the benefits of an optimized, native support for iterative array processing on the SciDB engine and real workloads from the astronomy domain.
  • The Thoracic and Cardiovascular Surgeon 01/2015; 63(S 01). DOI:10.1055/s-0035-1544479 · 0.98 Impact Factor
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    ABSTRACT: Objective: Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome. Approach and results: Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs. Conclusions: Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.
    Arteriosclerosis Thrombosis and Vascular Biology 10/2014; 35(1). DOI:10.1161/ATVBAHA.114.304364 · 6.00 Impact Factor
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    ABSTRACT: The LSST will, over a 10-year period, produce a multi-color, multi-epoch survey of more than 18000 square degrees of the southern sky. It will generate a multi-petabyte archive of images and catalogs of astrophysical sources from which a wide variety of high-precision statistical studies can be undertaken. To accomplish these goals, the LSST project has developed a suite of modeling and simulation tools for use in validating that the design and the as-delivered components of the LSST system will yield data products with the required statistical properties. In this paper we describe the development, and use of the LSST simulation framework, including the generation of simulated catalogs and images for targeted trade studies, simulations of the observing cadence of the LSST, the creation of large-scale simulations that test the procedures for data calibration, and use of end-to-end image simulations to evaluate the performance of the system as a whole.
    SPIE Astronomical Telescopes + Instrumentation; 08/2014
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    ABSTRACT: We describe the Metrics Analysis Framework (MAF), an open-source python framework developed to provide a user-friendly, customizable, easily-extensible set of tools for analyzing data sets. MAF is part of the Large Synoptic Survey Telescope (LSST) Simulations effort. Its initial goal is to provide a tool to evaluate LSST Operations Simulation (OpSim) simulated surveys to help understand the effects of telescope scheduling on survey performance, however MAF can be applied to a much wider range of datasets. The building blocks of the framework are Metrics (algorithms to analyze a given quantity of data), Slicers (subdividing the overall data set into smaller data slices as relevant for each Metric), and Database classes (to access the dataset and read data into memory). We describe how these building blocks work together, and provide an example of using MAF to evaluate different dithering strategies. We also outline how users can write their own custom Metrics and use these within the framework.
    SPIE Astronomical Telescopes + Instrumentation; 07/2014
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    ABSTRACT: The requirement and influence of the peripheral nervous system on tissue replacement in mammalian appendages remain largely undefined. To explore this question, we have performed genetic lineage tracing and clonal analysis of individual cells of mouse hind limb tissues devoid of nerve supply during regeneration of the digit tip, normal maintenance, and cutaneous wound healing. We show that cellular turnover, replacement, and cellular differentiation from presumed tissue stem/progenitor cells within hind limb tissues remain largely intact independent of nerve and nerve-derived factors. However, regenerated digit tips in the absence of nerves displayed patterning defects in bone and nail matrix. These nerve-dependent phenotypes mimic clinical observations of patients with nerve damage resulting from spinal cord injury and are of significant interest for translational medicine aimed at understanding the effects of nerves on etiologies of human injury.
    Proceedings of the National Academy of Sciences 06/2014; 111(27). DOI:10.1073/pnas.1410097111 · 9.67 Impact Factor
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    ABSTRACT: -Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome (MFS). The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using magnetic resonance imaging (MRI) with a gadolinium-based elastin-specific contrast agent (ESMA) in Fbn1(C1039G/+) mice. -Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (WT) (n=9 and n=10, respectively) using 7T MRI with a T1-mapping sequence. Significantly lower enhancement (i.e., lower R1 values, where R1=1/T1) was detected post-ESMA in Fbn1(C1039G/+) compared to WT ascending aortas (1.15±0.07 vs. 1.36±0.05, p<0.05). Post-ESMA R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (p=0.006). -Herein, we demonstrate that MRI with ESMA accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared to WT controls. This approach has translational potential for non-invasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions.
    Circulation Cardiovascular Imaging 05/2014; 7(4). DOI:10.1161/CIRCIMAGING.114.001658 · 5.32 Impact Factor
  • Pramod Gupta · Andrew J. Connolly · Jeffrey P. Gardner
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    ABSTRACT: Future astronomical surveys will produce data on similar to 10(8) objects per night. In order to characterize and classify these sources, we will require algorithms that scale linearly with the size of the data, that can be easily parallelized and where the speedup of the parallel algorithm will be linear in the number of processing cores. In this paper, we present such an algorithm and apply it to the question of colour selection of quasars. We use non-parametric Bayesian classification and a binning algorithm implemented with hash tables (BASH tables). We show that this algorithm's run time scales linearly with the number of test set objects and is independent of the number of training set objects. We also show that it has the same classification accuracy as other algorithms. For current data set sizes, it is up to three orders of magnitude faster than commonly used naive kernel-density-estimation techniques and it is estimated to be about eight times faster than the current fastest algorithm using dual kd-trees for kernel density estimation. The BASH table algorithm scales linearly with the size of the test set data only, and so for future larger data sets, it will be even faster compared to other algorithms which all depend on the size of the test set and the size of the training set. Since it uses linear data structures, it is easier to parallelize compared to tree-based algorithms and its speedup is linear in the number of cores unlike tree-based algorithms whose speedup plateaus after a certain number of cores. Moreover, due to the use of hash tables to implement the binning, the memory usage is very small. While our analysis is for the specific problem of selection of quasars, the ideas are general and the BASH table algorithm can be applied to any density-estimation problem involving sparse high-dimensional data sets. Since sparse high-dimensional data sets are a common type of scientific data set, this method has the potential to be useful in a broad range of machine-learning applications in astrophysics.
    Monthly Notices of the Royal Astronomical Society 02/2014; 439(1):644-650. DOI:10.1093/mnras/stt2490 · 5.11 Impact Factor
  • Jake Vander Plas · A. J. Connolly · Z. Ivezic
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    ABSTRACT: As astronomical data sets grow in size and complexity, automated machine learning and data mining methods are becoming an increasingly fundamental component of research in the field. The astroML project (http://astroML.org) provides a common repository for practical examples of the data mining and machine learning tools used and developed by astronomical researchers, written in Python. The astroML module contains a host of general-purpose data analysis and machine learning routines, loaders for openly-available astronomical datasets, and fast implementations of specific computational methods often used in astronomy and astrophysics. The associated website features hundreds of examples of these routines being used for analysis of real astronomical datasets, while the associated textbook provides a curriculum resource for graduate-level courses focusing on practical statistics, machine learning, and data mining approaches within Astronomical research. This poster will highlight several of the more powerful and unique examples of analysis performed with astroML, all of which can be reproduced in their entirety on any computer with the proper packages installed.
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    ABSTRACT: With upcoming all sky surveys such as LSST poised to generate a deep digital movie of the optical sky, variability-based AGN selection will enable the construction of highly-complete catalogs with minimum contamination. In this study, we generate $g$-band difference images and construct light curves for QSO/AGN candidates listed in SDSS Stripe 82 public catalogs compiled from different methods, including spectroscopy, optical colors, variability, and X-ray detection. Image differencing excels at identifying variable sources embedded in complex or blended emission regions such as Type II AGNs and other low-luminosity AGNs that may be omitted from traditional photometric or spectroscopic catalogs. To separate QSOs/AGNs from other sources using our difference image light curves, we explore several light curve statistics and parameterize optical variability by the characteristic damping timescale ($\tau$) and variability amplitude. By virtue of distinguishable variability parameters of AGNs, we are able to select them with high completeness of 93.4% and efficiency (i.e., purity) of 71.3%. Based on optical variability, we also select highly variable blazar candidates, whose infrared colors are consistent with known blazars. One third of them are also radio detected. With the X-ray selected AGN candidates, we probe the optical variability of X-ray detected optically-extended sources using their difference image light curves for the first time. A combination of optical variability and X-ray detection enables us to select various types of host-dominated AGNs. Contrary to the AGN unification model prediction, two Type II AGN candidates (out of 6) show detectable variability on long-term timescales like typical Type I AGNs. This study will provide a baseline for future optical variability studies of extended sources.
    The Astrophysical Journal 12/2013; 782(1). DOI:10.1088/0004-637X/782/1/37 · 5.99 Impact Factor
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    ABSTRACT: This document presents (off-line) computing requrements and challenges for Cosmic Frontier science, covering the areas of data management, analysis, and simulations. We invite contributions to extend the range of covered topics and to enhance the current descriptions.
  • Circulation Journal 10/2013; 78(2). DOI:10.1253/circj.CJ-13-0708 · 3.94 Impact Factor
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    ABSTRACT: The quantity and quality of cosmic structure observations have greatly accelerated in recent years. Further leaps forward will be facilitated by imminent projects, which will enable us to map the evolution of dark and baryonic matter density fluctuations over cosmic history. The way that these fluctuations vary over space and time is sensitive to the nature of dark matter and dark energy. Dark energy and gravity both affect how rapidly structure grows; the greater the acceleration, the more suppressed the growth of structure, while the greater the gravity, the more enhanced the growth. While distance measurements also constrain dark energy, the comparison of growth and distance data tests whether General Relativity describes the laws of physics accurately on large scales. Modified gravity models are able to reproduce the distance measurements but at the cost of altering the growth of structure (these signatures are described in more detail in the accompanying paper on Novel Probes of Gravity and Dark Energy). Upcoming surveys will exploit these differences to determine whether the acceleration of the Universe is due to dark energy or to modified gravity. To realize this potential, both wide field imaging and spectroscopic redshift surveys play crucial roles. Projects including DES, eBOSS, DESI, PFS, LSST, Euclid, and WFIRST are in line to map more than a 1000 cubic-billion-light-year volume of the Universe. These will map the cosmic structure growth rate to 1% in the redshift range 0<z<2, over the last 3/4 of the age of the Universe.
    Astroparticle Physics 09/2013; 63. DOI:10.1016/j.astropartphys.2014.07.004 · 3.58 Impact Factor
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    ABSTRACT: In this demonstration, we present AscotDB, a new tool for the analysis of telescope image data. AscotDB results from the integration of ASCOT, a Web-based tool for the collaborative analysis of telescope images and their metadata, and SciDB, a parallel array processing engine. We demonstrate the novel data exploration supported by this integrated tool on a 1 TB dataset comprising scientifically accurate, simulated telescope images. We also demonstrate novel iterative-processing features that we added to SciDB in order to support this use-case.
    Proceedings of the VLDB Endowment 08/2013; 6(12):1322-1325. DOI:10.14778/2536274.2536306
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    ABSTRACT: Most quasars are known to be variable and they show larger variability on longer timescales of months to years. In this study, we generate g-band difference images and construct light curves for QSO/AGN candidates listed in Stripe 82 public catalogs complied from different methods, including spectroscopy, colors, variability, and X-ray detection. To separate QSOs/AGNs from other (non-)variable sources, we quantify their variability in the characteristic timescales (τ) and amplitude (SF∞) using the first-order structure function (SF) for the damped random walk (DRW) model. We find that QSOs occupy a specific region in the SF parameter space, enabling us to identify them with high efficiency and completeness. Since difference imaging excels at identifying variable sources embedded in complex or blended emission regions, it is one of the best tools to examine the variability of active nuclei surrounded by host galaxy emission, i.e. type II AGNs, and lower-luminosity AGNs. For the first time, we probe the variability of X-ray detected extended sources using their difference imaging light curves. Contrary to the AGN unification model prediction, some type II AGNs show detectable variability on long-term timescales like typical QSOs/AGNs.
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    ABSTRACT: Although mechanical osteotomies are frequently made on the craniofacial skeleton, collateral thermal, and mechanical trauma to adjacent bone tissue causes cell death and may delay healing. The present study evaluated the use of plasma-mediated laser ablation using a femtosecond laser to circumvent thermal damage and improve bone regeneration. Critical-size circular calvarial defects were created with a trephine drill bit or with a Ti:Sapphire femtosecond pulsed laser. Healing was followed using micro-CT scans for 8 weeks. Calvaria were also harvested at various time points for histological analysis. Finally, scanning electron microscopy was used to analyze the microstructure of bone tissue treated with the Ti:Sapphire laser, and compared to that treated with the trephine bur. Laser-created defects healed significantly faster than those created mechanically at 2, 4, and 6 weeks post-surgery. However, at 8 weeks post-surgery, there was no significant difference. In the drill osteotomy treatment group, empty osteocyte lacunae were seen to extend 699 ± 27 µm away from the edge of the defect. In marked contrast, empty osteocyte lacunae were seen to extend only 182 ± 22 µm away from the edge of the laser-created craters. Significantly less ossification and formation of irregular woven bone was noted on histological analysis for drill defects. We demonstrate accelerated bone healing after femtosecond laser ablation in a calvarial defect model compared to traditional mechanical drilling techniques. Improved rates of early regeneration make plasma-mediated ablation of the craniofacial skeleton advantageous for applications to osteotomy. Lasers Surg. Med. 44: 805–814, 2012.
    Lasers in Surgery and Medicine 12/2012; 44(10). DOI:10.1002/lsm.22098 · 2.62 Impact Factor
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    ABSTRACT: This paper describes the Fourth Data Release of the Sloan Digital Sky Survey (SDSS), including all survey-quality data taken through 2004 June. The data release includes five-band photometric data for 180 million objects selected over 6670 deg2 and 673,280 spectra of galaxies, quasars, and stars selected from 4783 deg2 of those imaging data using the standard SDSS target selection algorithms. These numbers represent a roughly 27% increment over those of the Third Data Release; all the data from previous data releases are included in the present release. The Fourth Data Release also includes an additional 131,840 spectra of objects selected using a variety of alternative algorithms, to address scientific issues ranging from the kinematics of stars in the Milky Way thick disk to populations of faint galaxies and quasars.
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    ABSTRACT: Pluripotent cells represent a powerful tool for tissue regeneration, but their clinical utility is limited by their propensity to form teratomas. Little is known about their interaction with the surrounding niche following implantation and how this may be applied to promote survival and functional engraftment. In this study, we evaluated the ability of an osteogenic microniche consisting of a hydroxyapatite-coated, bone morphogenetic protein-2-releasing poly-l-lactic acid scaffold placed within the context of a macroenvironmental skeletal defect to guide in vivo differentiation of both embryonic and induced pluripotent stem cells. In this setting, we found de novo bone formation and participation by implanted cells in skeletal regeneration without the formation of a teratoma. This finding suggests that local cues from both the implanted scaffold/cell micro- and surrounding macroniche may act in concert to promote cellular survival and the in vivo acquisition of a terminal cell fate, thereby allowing for functional engraftment of pluripotent cells into regenerating tissue.
    Proceedings of the National Academy of Sciences 11/2012; 109(50). DOI:10.1073/pnas.1218052109 · 9.67 Impact Factor

Publication Stats

23k Citations
1,037.05 Total Impact Points


  • 1995–2015
    • Stanford Medicine
      • • Department of Pathology
      • • Department of Developmental Biology
      • • Division of Cardiovascular Medicine
      Stanford, California, United States
  • 2007–2014
    • University of Washington Seattle
      • Department of Astronomy
      Seattle, Washington, United States
  • 2003–2014
    • Stanford University
      • Division of Cardiovascular Medicine
      Palo Alto, California, United States
    • Palo Alto Medical Foundation
      Palo Alto, California, United States
    • The University of Tokyo
      • Institute for Cosmic Ray Research
      Tokyo, Tokyo-to, Japan
  • 1994–2012
    • Space Telescope Science Institute
      Baltimore, Maryland, United States
  • 2009
    • University of Illinois, Urbana-Champaign
      • Department of Astronomy
      Urbana, Illinois, United States
    • American University Washington D.C.
      Washington, Washington, D.C., United States
  • 2001–2008
    • University of Pittsburgh
      • Physics and Astronomy
      Pittsburgh, PA, United States
    • Fermi National Accelerator Laboratory (Fermilab)
      Batavia, Illinois, United States
  • 2006
    • Lawrence Berkeley National Laboratory
      Berkeley, California, United States
    • Princeton University
      • Department of Astrophysical Sciences
      Princeton, New Jersey, United States
    • The University of Arizona
      • Department of Computer Science
      Tucson, Arizona, United States
  • 1997–2006
    • Johns Hopkins University
      • Department of Physics and Astronomy
      Baltimore, Maryland, United States
  • 2005
    • Massachusetts Institute of Technology
      • Department of Physics
      Cambridge, Massachusetts, United States
  • 2001–2003
    • Carnegie Mellon University
      • Department of Physics
      Pittsburgh, Pennsylvania, United States
  • 2002
    • University of Chicago
      • Department of Astronomy and Astrophysics
      Chicago, Illinois, United States
    • University of Santiago, Chile
      • Departamento de Economía
      CiudadSantiago, Santiago, Chile
  • 1999
    • Eötvös Loránd University
      • Department of Physics of Complex Systems
      Budapeŝto, Budapest, Hungary
  • 1992–1997
    • University of California, San Francisco
      • • Department of Pathology
      • • Cardiovascular Research Institute
      San Francisco, CA, United States