114 results on '"Ryan, Murray"'
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2. Using Skew to Assess the Quality of GAN-generated Image Features.
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Lorenzo Luzi, Helen Jenne, Carlos Ortiz Marrero, and Ryan Murray 0001
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- 2024
3. Uniform Convergence of Adversarially Robust Classifiers.
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Rachel Morris and Ryan Murray 0001
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- 2024
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4. Home Dialysis Training Needs for Fellows: A Survey of Nephrology Program Directors and Division Chiefs in the United States
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Yuvaram N.V. Reddy, MBBS, MPH, Jeffrey S. Berns, MD, Shweta Bansal, MD, James F. Simon, MD, Ryan Murray, Molly Jacob, Jeffrey Perl, MD, MS, and Edward Gould, MD
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Diseases of the genitourinary system. Urology ,RC870-923 - Published
- 2023
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5. Adversarial Classification: Necessary Conditions and Geometric Flows.
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Nicolás García Trillos and Ryan Murray 0001
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- 2022
6. Distributed Stochastic Gradient Descent: Nonconvexity, Nonsmoothness, and Convergence to Local Minima.
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Brian Swenson, Ryan Murray 0001, H. Vincent Poor, and Soummya Kar
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- 2022
7. Dirichlet Active Learning.
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Kevin Miller and Ryan Murray 0001
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- 2023
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8. Using Higher-Order Moments to Assess the Quality of GAN-generated Image Features.
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Lorenzo Luzi, Helen Jenne, Ryan Murray 0001, and Carlos Ortiz Marrero
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- 2023
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9. Arthroscopic Repair of a Type VIII Superior Labrum Anterior Posterior Tear
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Michael Nammour MD, Justin W. Arner MD, Ryan Murray MD, and James P. Bradley MD
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Sports medicine ,RC1200-1245 ,Orthopedic surgery ,RD701-811 - Abstract
Background: Type VIII superior labrum anterior posterior (SLAP) tears are described as SLAP type II tears with posterior extension to the posterior inferior glenohumeral ligament. These tears are a common source of pain, instability, and decreased function in active individuals, particularly overhead or throwing athletes. Indications: Type VIII SLAP tears can cause pain and loss of sports performance, especially in a throwing athlete. This patient is a quarterback and pitcher who had magnetic resonance imaging and arthroscopic evidence of a type VIII SLAP tear with pain and inability to throw at his preinjury level. Technique Description: In the lateral decubitus position, a standard posterior portal is established along with anterior and accessory lateral portals. A type VIII SLAP tear is identified and the arm is taken out of balanced suspension traction and placed in abduction and external rotation which shows displacement of the posterior labrum and peelback of the superior labrum indicating pathologic labral instability. The labrum is then elevated and glenoid prepared to achieve healthy bleeding bone. Tape sutures are then passed around the labrum and placed into a glenoid anchor starting superiorly and continuing the repair posteroinferiorly. Three anchors were placed in the superior labrum using a percutaneous technique, with 2 more placed from the posterior portal to complete the 5-anchor repair. The posterior portal is then closed with a single monofilament suture to prevent a potential stress riser in the capsule. Results: The literature suggests that athletes with type VIII SLAP tears can expect improved functional outcomes and high return to play rates (>90%); however, only 50% to 70% of throwing athletes return to the same level of play. Discussion/Conclusion: Type VIII SLAP tears are an important cause of shoulder pain and dysfunction, particularly in overhead athletes. Arthroscopic repair of type VIII SLAP tears can improve functional outcomes and ability to return to sport; however, throwing athletes experience lower rates of return to previous level. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.
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- 2023
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10. Scapulothoracic Arthroscopy for Snapping Scapula Syndrome
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Michael Nammour MD, Justin Arner MD, Ryan Murray MD, and James Bradley MD
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Sports medicine ,RC1200-1245 ,Orthopedic surgery ,RD701-811 - Abstract
Background: Snapping scapula syndrome (SSS) is a disruption of the normal smooth motion of the scapulothoracic joint leading to clicking or “snapping” which can be painful or painless. There are a variety of etiologies with first-line treatment being conservative. If patients fail extensive nonoperative treatments, then surgery may be considered. Although technically challenging, arthroscopic treatment is recommended due to its decreased morbidity and improved cosmesis. Indications: We present a 21-year-old man with a 2-year history of mechanical popping and crepitus with overhead and scapulothoracic motion of his left arm. After failing an extensive trial of conservative therapy, the patient underwent scapulothoracic arthroscopy with bursectomy and partial resection of the superomedial border of the scapula. Technique Description: The patient is positioned prone with the operative arm behind the back to elevate the medial border off the chest wall. The scapula is outlined. Two arthroscopic portals are used; the superior portal is 3 cm medial to the medial border of the scapula at the level of the scapular spine and the inferior portal is 4 cm inferior to this at the inferomedial angle of the scapula. Viewing is typically done from the inferior portal, and the superior portal is used for resection of the bursa and superomedial border of the scapula. A shaver and ablator are used to perform a bursectomy and expose the superomedial border of the scapula. An arthroscopic bur is used to partially resect the superomedial border of the scapula at approximately 3.5 cm wide and 2 cm deep. Results: Although there are limited studies examining outcomes after scapulothoracic arthroscopy, the current literature suggests that scapulothoracic arthroscopy is effective in improving crepitus, pain, and clinical outcome scores. Discussion/Conclusion: In cases of SSS which have failed exhaustive conservative therapy, arthroscopic bursectomy and partial bony resection can be an effective treatment option with minimal invasiveness, improved cosmesis, and early return to activities. Proper patient positioning and careful portal placement are critical to avoid iatrogenic injury, particularly to neurologic structures. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.
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- 2023
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11. Arthroscopic Double-Row Rotator Cuff Repair With Box Configuration
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Soheil Sabzevari MD, Ryan Murray MD, Shaquille Charles MSc, Rajiv P. Reddy MSc, and Albert Lin MD
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Sports medicine ,RC1200-1245 ,Orthopedic surgery ,RD701-811 - Abstract
Background: Arthroscopic transosseous-equivalent (TOE) techniques may offer additional advantages, including a more efficient surgery with a self-reinforcing construct with equivalent clinical results to medial knotted TOE repair for rotator cuff tears (RCTs). Indications: An arthroscopic knotless double-row (DR) rotator cuff repair (RCR) using FiberTak RC anchors for medial row fixation with box configuration may be an appropriate construct for operatively indicated small-to-moderate full-thickness RCTs. Technique: Our modified technique uses TOE repair principles to address RCTs too small for traditional 4.75-mm anchors using medial row fixation and too large to apply a single medial to lateral anchor repair. The patient is placed in a beach chair position. In addition to standard anterior and posterior portals, a lower lateral working portal and a higher posterolateral viewing portal are made. Subsequent to supraspinatus footprint visualization/preparation, two 2.6-mm FiberTak RC anchors each loaded with 1 LabralTape and 1 FiberWire are placed medially. The 4 sets of sutures for one anchor are placed through the rotator cuff tendon together in 1 spot and the process is repeated for the second anchor. One FiberWire from each anchor is then tied extracorporeally and then a double pulley technique is used to compress the medial aspect of the repair at the footprint in a box configuration. Finally, 1 limb of LabralTape from each of the medial anchors along with the corresponding FiberWire is secured through 2 lateral-row 4.75-mm anchors anteriorly and posteriorly to restore the lateral footprint and secure the rotator cuff in TOE box configuration. This modified technique can provide anatomical compression of the rotator cuff tendon at the footprint with additional medial compression achieved by the box configuration while taking advantage of knotless fixation. Results: Postoperatively, a sling is worn for 4 weeks, passive range of motion (ROM) is initiated at 2 weeks, active ROM is begun at 6 weeks, and strengthening at 3 months. Patients may return to full unrestricted activities around 5 to 6 months. Discussion/Conclusion: A modified arthroscopic DR RCR with box configuration is an excellent treatment option for patients with small-to-moderate full-thickness RCT who fail conservative treatment. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.
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- 2023
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12. Rates of Convergence for Regression with the Graph Poly-Laplacian.
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Nicolás García Trillos, Ryan Murray 0001, and Matthew Thorpe
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- 2022
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13. Tubbataha Reefs Natural Park: the first comprehensive elasmobranch assessment reveals global hotspot for reef sharks
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Ryan Murray, Segundo Conales, Jr., Gonzalo Araujo, Jessica Labaja, Sally J. Snow, Simon J. Pierce, Angelique Songco, and Alessandro Ponzo
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Ecology ,QH540-549.5 - Abstract
Elasmobranchs are experiencing population declines worldwide because of anthropogenic stressors. Marine protected areas (MPAs) have been shown to benefit mesopredatory species of shark. The Tubbataha Reefs Natural Park (TRNP) is a United Nations Educational, Scientific and Cultural Organization World Heritage Site and the largest no-take MPA in the Philippines, yet information on the current status of elasmobranchs in the park is limited. Here, we investigate the abundance and biodiversity of elasmobranchs in TRNP using underwater visual census (UVC) and baited remote underwater video (BRUV) surveys. Twenty UVC were conducted in May 2015 (n = 10) and June 2016 (n = 10), documenting eight species of elasmobranchs with an average density of 7.18 sharks ha-1 for both years. A total of 113 successful BRUV surveys were conducted in TRNP between March–June 2015 (n = 47) and April–June 2016 (n = 66). The BRUV surveys recorded 14 species with an average catch per unit effort of 2.09 elasmobranchs per hour for both years. Both survey methods report some of the highest densities of the grey reef shark Carcharhinus amblyrhynchos and the whitetip reef shark Triaenodon obesus documented worldwide. This study underlines the importance of large, well-managed MPAs such as TRNP for the conservation of reef-associated elasmobranchs. Keywords: Baited remote underwater video, Elasmobranch conservation, Marine protected area, Reef sharks, Southeast Asia
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- 2019
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14. The Geometry of Adversarial Training in Binary Classification.
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Leon Bungert, Nicolás García Trillos, and Ryan Murray 0001
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- 2021
15. Adversarial Classification: Necessary conditions and geometric flows.
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Nicolás García Trillos and Ryan Murray 0001
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- 2020
16. From graph cuts to isoperimetric inequalities: Convergence rates of Cheeger cuts on data clouds.
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Nicolás García Trillos, Ryan Murray 0001, and Matthew Thorpe
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- 2020
17. Neural Basis of Internal Attention in Adults with Pure and Comorbid ADHD
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Halima Rafi, Ryan Murray, Farnaz Delavari, Nader Perroud, Patrik Vuilleumier, Martin Debbané, and Camille Piguet
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deficit hyperactivity disorder ,fmri ,brain ,temporal receptive windows ,interoception ,anterior insula ,comorbidity ,Clinical Psychology ,children ,networks ,Developmental and Educational Psychology ,adult adhd ,activation ,emotional dysregulation ,deficit/hyperactivity disorder - Abstract
Objective: To examine whether putatively atypical neuronal activity during internal attention in ADHD yields insights into processes underlying emotion dysregulation. Methods: We used a word processing paradigm to assess neural activations in adults with ADHD ( N = 46) compared to controls ( N = 43). We measured effects of valence, applied partial-least squares correlation analysis to assess multivariate brainbehavior relationships and ran subgroup analyses to isolate results driven by pure ADHD ( N = 18). Results: During internal attention, ADHD, compared to controls, have (1) increased activation in the right angular gyrus (rAG), which appears driven by pure, not comorbid, ADHD and (2) diminished activation in the insula and fronto-striatal circuitry. Diminished activations were driven by negatively-valenced internal attention and negatively correlated with increased affective lability within the ADHD group. Conclusion: Internal attention in ADHD is associated with increased rAG activation, possibly reflecting difficulty converging external and internal information, and diminished activation within emotion regulation circuitry.
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- 2023
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18. 111 Highly efficient multiplexed base editing enables development of universal CD7-targeting CAR-T Cells to treat T-ALL
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Sarah Smith, Alden Ladd, Jason Gehrke, Aaron Edwards, Ryan Murray, Angelica Messana, Lindsey Coholan, Henry Poulin, Melissa Le, Mark Naniong, Faith Musenge, Adam Camblin, Yeh-Chuin Poh, and Giuseppe Ciaramella
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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19. Occurrence of the rare and Endangered Ornate Eagle Ray, Aetomylaeus vespertilio (Bleeker, 1852) (Chondrichthyes, Myliobatidae), at a remote marine protected area in the Philippines
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Gonzalo Araujo, Sally J. Snow, Andy Cornish, Ryan Murray, Kymry Delijero, Alessandro Ponzo, and Marivel Dygico
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Biology (General) ,QH301-705.5 - Abstract
We report the occurrence of the rare and Endangered Aetomylaeus vespertilio (Bleeker, 1852) at the remote archipelago of Cagayancillo, Palawan in the Sulu Sea, Philippines. Only 1 previous report of the species exists from the country, a juvenile specimen in the Pasil market, Cebu City in 2000. During an in-water shark and ray survey at Cagayancillo Island in April 2017, a female individual A. vespertilio with a disc width of approximately 200 cm, and a total length of approximately 400 cm was encountered along the reef’s edge at a depth of 12 m. This species wasconfirmed by its characteristic dorsal pattern of narrow stripes anteriorly and reticulated spots posteriorly. We confirm the occurrence of this rare and poorly understood species in the Sulu Sea and extend the current known range farther west than previously known.
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- 2018
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20. A maximum principle argument for the uniform convergence of graph Laplacian regressors.
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Nicolás García Trillos and Ryan Murray 0001
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- 2019
21. Tukey Depths and Hamilton--Jacobi Differential Equations
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Martin Molina-Fructuoso and Ryan Murray
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FOS: Computer and information sciences ,Computer Science - Machine Learning ,Mathematics - Analysis of PDEs ,Statistics - Machine Learning ,FOS: Mathematics ,Machine Learning (stat.ML) ,Mathematics - Statistics Theory ,Statistics Theory (math.ST) ,General Medicine ,General Chemistry ,Machine Learning (cs.LG) ,Analysis of PDEs (math.AP) - Abstract
The widespread application of modern machine learning has increased the need for robust statistical algorithms. This work studies one such fundamental statistical measure known as the Tukey depth. We study the problem in the continuum (population) limit. In particular, we derive the associated necessary conditions, which take the form of a first-order partial differential equation. We discuss the classical interpretation of this necessary condition as the viscosity solution of a Hamilton-Jacobi equation, but with a non-classical Hamiltonian with discontinuous dependence on the gradient at zero. We prove that this equation possesses a unique viscosity solution and that this solution always bounds the Tukey depth from below. In certain cases, we prove that the Tukey depth is equal to the viscosity solution, and we give some illustrations of standard numerical methods from the optimal control community which deal directly with the partial differential equation. We conclude by outlining several promising research directions both in terms of new numerical algorithms and theoretical challenges.
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- 2022
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22. From Graph Cuts to Isoperimetric Inequalities: Convergence Rates of Cheeger Cuts on Data Clouds
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Nicolás García Trillos, Ryan Murray, and Matthew Thorpe
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Computational Geometry (cs.CG) ,FOS: Computer and information sciences ,Computer Science - Machine Learning ,Mechanical Engineering ,49Q20 ,Machine Learning (stat.ML) ,Computer Science::Digital Libraries ,Machine Learning (cs.LG) ,Mathematics - Spectral Theory ,Mathematics - Analysis of PDEs ,Mathematics (miscellaneous) ,Statistics - Machine Learning ,FOS: Mathematics ,Computer Science - Computational Geometry ,Mathematics::Differential Geometry ,Spectral Theory (math.SP) ,Analysis ,Analysis of PDEs (math.AP) - Abstract
In this work we study statistical properties of graph-based clustering algorithms that rely on the optimization of balanced graph cuts, the main example being the optimization of Cheeger cuts. We consider proximity graphs built from data sampled from an underlying distribution supported on a generic smooth compact manifold $${\mathcal {M}}$$ M . In this setting, we obtain high probability convergence rates for both the Cheeger constant and the associated Cheeger cuts towards their continuum counterparts. The key technical tools are careful estimates of interpolation operators which lift empirical Cheeger cuts to the continuum, as well as continuum stability estimates for isoperimetric problems. To the best of our knowledge the quantitative estimates obtained here are the first of their kind.
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- 2022
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23. Merchandise sales rank in professional sport : Purchase drivers and implications for National Hockey League clubs
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Norm O'Reilly, George Foster, Ryan Murray, and Carlos Shimizu
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- 2015
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24. Life History, Growth, and Reproductive Biology of Four Mobulid Species in the Bohol Sea, Philippines
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Joshua M. Rambahiniarison, Mary Jane Lamoste, Christoph A. Rohner, Ryan Murray, Sally Snow, Jessica Labaja, Gonzalo Araujo, and Alessandro Ponzo
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elasmobranchs ,sexual maturity ,reproduction ,intrinsic growth rate ,population doubling time ,Science ,General. Including nature conservation, geographical distribution ,QH1-199.5 - Abstract
In light of the global decline of mobulid populations and the necessity for sustainable fisheries management, baseline data for population dynamics were collected from a targeted fishery in the Bohol Sea, Philippines. This study focused on life-history parameters and reproductive cycles of four mobulid rays (Mobula thurstoni, Mobula japanica, Mobula tarapacana, and Manta birostris), and re-estimated their intrinsic population growth rates. Size and reproductive data were collected from 1,509 specimens (30% of catch) landed in two fishing seasons in 2015 and 2016. Size-at-birth was reviewed, and analysis of the embryos and follicles did not show any clear seasonality in the reproductive cycle, but supported an interbreeding interval. Females of all species matured at a larger size than males, and exhibited a larger size-at-pregnancy than -at-maturity. This delay in reproduction resulted in population growth rates lower than the actual rmax when based on size-at-pregnancy (rmat = rmax = 0.016–0.055 year−1 and rpreg = 0.008–0.044 year−1), and a population doubling time of 15.8–86.6 years. This study suggests that population growth rates previously reported were overestimated. In light of the Convention on International Trades of Endangered Species (CITES) and Convention on Migratory Species (CMS) assessments, while fisheries management should reflect the delayed maturation of these species and the slower population growth potential, at the current status of these population, the sustainability of any exploitation level seems unrealistic and strongly discouraged.
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- 2018
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25. Satellite tracking of juvenile whale sharks in the Sulu and Bohol Seas, Philippines
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Gonzalo Araujo, Christoph A. Rohner, Jessica Labaja, Segundo J. Conales, Sally J. Snow, Ryan Murray, Simon J. Pierce, and Alessandro Ponzo
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Ecology ,Movement patterns ,Telemetry ,Satellite tagging ,Endangered ,Distribution ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
The whale shark Rhincodon typus was uplisted to ‘Endangered’ in the 2016 IUCN Red List due to >50% population decline, largely caused by continued exploitation in the Indo-Pacific. Though the Philippines protected the whale shark in 1998, concerns remain due to continued take in regional waters. In light of this, understanding the movements of whale sharks in the Philippines, one of the most important hotspots for the species, is vital. We tagged 17 juvenile whale sharks with towed SPOT5 tags from three general areas in the Sulu and Bohol Seas: Panaon Island in Southern Leyte, northern Mindanao, and Tubbataha Reefs Natural Park (TRNP). The sharks all remained in Philippine waters for the duration of tracking (6–126 days, mean 64). Individuals travelled 86–2,580 km (mean 887 km) at a mean horizontal speed of 15.5 ± 13.0 SD km day−1. Whale sharks tagged in Panaon Island and Mindanao remained close to shore but still spent significant time off the shelf (>200 m). Sharks tagged at TRNP spent most of their time offshore in the Sulu Sea. Three of twelve whale sharks tagged in the Bohol Sea moved through to the Sulu Sea, whilst two others moved east through the Surigao Strait to the eastern coast of Leyte. One individual tagged at TRNP moved to northern Palawan, and subsequently to the eastern coast of Mindanao in the Pacific Ocean. Based on inferred relationships with temperature histograms, whale sharks performed most deep dives (>200 m) during the night, in contrast to results from whale sharks elsewhere. While all sharks stayed in national waters, our results highlight the high mobility of juvenile whale sharks and demonstrate their connectivity across the Sulu and Bohol Seas, highlighting the importance of the area for this endangered species.
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- 2018
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26. Keep Pies Away from Kids: A Raspberry Pi Attacking Tool.
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Antonis Michalas and Ryan Murray 0002
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- 2017
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27. The Appraising Brain: intrinsic motivation modulates amygdala response to otherwise neutral stimuli
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Ryan Murray, Hana H Kutlikova, Tobias Brosch, and David Sander
- Abstract
Based on an affective neuroscience approach to appraisal theories of emotion, the present study tested the hypothesis that the amygdala is involved in the processing of concern-relevance. Thirty-five students with varying intrinsic academic intrinsic motivation performed three target detection tasks (i.e. targets vs. nontargets) using affectively neutral letter stimuli as targets. In one task, participants were given a cover story that their task-performance was indicative of future academic success. This intrinsic motivation task was controlled with two other tasks: an extrinsic motivation task allowing participants to earn money for themselves based on their task-performance, and a baseline task where participants were simply requested to perform the task while we were calibrating the scanner. Results illustrated an interaction effect both at the whole-brain and region-of-interest levels. When accounting for all three conditions, only during the intrinsic motivation condition did bilateral amygdala activation significantly increase with increasing academic intrinsic motivation scores when responding to targets (versus nontargets). Findings suggest inter-individual intrinsic motivations modulate amygdala response to otherwise neutral stimuli, consistently with the proposal that the amygdala is sensitive to the degree to which stimuli are relevant to the individual’s concerns. This stresses the need for more personalized analyses of brain responses to stimuli and tasks that are typically considered as “neutral” and hold important implications for psychiatric populations suffering from deficiencies in affective processing, particularly anxiety disorders.
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- 2022
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28. Differential influence of habitual behavior components on compulsive and problematic reward-seeking behavior
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Lavinia Wuensch, Yoann Stussi, Ryan Murray, Maelys Denis-Bonnin, Tamara Corino, David Sander, Julie Péron, and eva pool
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Habitual behavior has been identified as a key process involved in a variety of mental health disorders. Previous research has shown that habit is not a unitary construct. The present study examined how different components of habitual behavior relate to problematic reward-seeking behaviors and compulsive behaviors. Four hundred and one participants completed a French version of the Creature of Habit Scale, which measures two components of habitual behavior: routine and automaticity. Participants also completed questionnaires assessing compulsivity, impulsivity, stress, and a variety of problematic reward-seeking behaviors, from which five transdiagnostic factors were extracted using an exploratory factor analysis. A dynamic network analysis indicated that the two habitual behavior components were differentially related to these transdiagnostic factors: routine was associated to compulsivity, while automaticity was associated to problematic media consumption. These findings suggest that taking the non-unitary architecture of habit into account may help to better understand the role of habit in mental health.
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- 2022
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29. Feeding the world's largest fish: highly variable whale shark residency patterns at a provisioning site in the Philippines
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Jordan A. Thomson, Gonzalo Araujo, Jessica Labaja, Emer McCoy, Ryan Murray, and Alessandro Ponzo
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wildlife tourism ,supplemental feeding ,shark tourism ,shark diving ,habitat use ,elasmobranch ,Science - Abstract
Provisioning wildlife for tourism is a controversial yet widespread practice. We analysed the residency patterns of juvenile whale sharks (Rhincodon typus) in Oslob, Philippines, where provisioning has facilitated a large shark-watching operation since 2011. We identified 208 individual sharks over three years, with an average of 18.6 (s.d. = 7.8, range = 6–43) individuals sighted per week. Weekly shark abundance varied seasonally and peak-season abundance (approx. May–November) increased across years. Whale sharks displayed diverse individual site visitation patterns ranging from a single visit to sporadic visits, seasonal residency and year-round residency. Nine individuals became year-round residents, which represents a clear response to provisioning. The timing of the seasonal peak at Oslob did not align with known non-provisioned seasonal aggregations elsewhere in the Philippines, which could suggest that seasonal residents at Oslob exploit this food source when prey availability at alternative sites is low. Since prolonged residency equates to less time foraging naturally, provisioning could influence foraging success, alter distributions and lead to dependency in later life stages. Such impacts must be carefully weighed against the benefits of provisioning (i.e. tourism revenue in a remote community) to facilitate informed management decisions.
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- 2017
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30. Legal Tech and Sustainability
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Ryan Murray and Helen Edwards
- Published
- 2022
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31. Distribution of the reef manta ray Mobula alfredi and the oceanic manta ray Mobula birostris in the Philippines: A collaborative effort for conservation
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Joshua Rambahiniarison, Ariana Agustines, Konstantinos Alexopoulos, Gonzalo Araujo, Asia O. Armstrong, Shannon Arnold, Aldrin Barruga, Titus Cañete, Segundo Conales, Kymry Delijero, Nonie P. Enolva, Anna L. Flam, Eliya Keane, Jessica Labaja, Christine G. Legaspi, Calum Murie, Ryan Murray, Simon P. Oliver, Simon J. Pierce, Alessandro Ponzo, Christoph A. Rohner, Rosanna Schifferer, Sally Snow, Martina Spakowski, Guy M. W. Stevens, Timur Tilgel, Jessica N. C. Wong, Arnel Andrew Yaptinchay, and Yotam Barr
- Subjects
Aquatic Science ,Ecology, Evolution, Behavior and Systematics - Abstract
Little is known about manta ray population size, structure, and connectivity in the Philippines. In collaboration with dive operators, non-governmental organizations, and authorities, sightings of manta rays were collated into a single national database. Using in-water photographs and videos gathered through citizen science and dedicated research efforts, this study compiled sightings between 2004 and 2020, showing 22 separate sites throughout the archipelago with manta rays present. A total of 392 individual reef manta rays (Mobula alfredi) and 107 oceanic manta rays (Mobula birostris) were identified from the collected footage. Four specific sites in the provinces of Masbate and Palawan together hosted 87% of all identified individuals and accounted for 94% of sightings, highlighting these areas are key aggregation sites. This study also reports movements of M. birostris within the Philippines, based on photo-identification of three individuals moving 150 km between Cebu and Masbate. Despite the growing number of recreational divers in Daanbantayan and San Jacinto, an 80% decline in M. birostris sightings was observed at these sites. To ensure effective future conservation, it is recommended that efforts focus on the identification and protection of manta ray hotspots and migratory corridors, the creation of a sustainable tourism framework, and most importantly, on the implementation of mitigation strategies to reduce fisheries interactions.
- Published
- 2022
32. On self-similar solutions to the incompressible Euler equations
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Ryan Murray and Alberto Bressan
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Applied Mathematics ,010102 general mathematics ,Mathematical analysis ,Fixed point ,Vorticity ,01 natural sciences ,Domain (mathematical analysis) ,Vortex ,Euler equations ,010101 applied mathematics ,symbols.namesake ,Singularity ,Compressibility ,symbols ,Initial value problem ,0101 mathematics ,Analysis ,Mathematics - Abstract
Recent numerical simulations have shown the existence of multiple self-similar solutions to the Cauchy problem for the 2-dimensional incompressible Euler equation, with initial vorticity in L l o c p ( R 2 ) , 1 ≤ p + ∞ . Toward a rigorous validation of these computations, in this paper we analytically construct self-similar solutions (i) on an outer domain of the form { | x | > R } , and (ii) in a neighborhood of the points where the solution exhibits a spiraling vortex singularity. The outer solution is obtained as the fixed point of a contractive transformation, based on the Biot-Savart formula and integration along characteristics. The inner solution is constructed using a system of adapted coordinates, following the approach of V. Elling (2016) [17] .
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- 2020
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33. Directed evolution of adenine base editors with increased activity and therapeutic application
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Jonathan Yen, Giuseppe Ciaramella, Luis A. Barrera, Aaron Edwards, Alexander Liquori, Nicole M. Gaudelli, Dieter K. Lam, Holly A. Rees, Noris M. Solá-Esteves, Lauren Young, Jason Michael Gehrke, Conrad Rinaldi, Michael S. Packer, Seung-Joo Lee, Ian Slaymaker, Ryan Murray, and David A. Born
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HBG1 ,Biomedical Engineering ,Deamination ,Bioengineering ,Biology ,Applied Microbiology and Biotechnology ,03 medical and health sciences ,Adenosine deaminase ,0302 clinical medicine ,Guide RNA ,Gene ,030304 developmental biology ,0303 health sciences ,Messenger RNA ,Chemistry ,Point mutation ,RNA ,Directed evolution ,Molecular biology ,Cell biology ,genomic DNA ,Protospacer adjacent motif ,biology.protein ,Molecular Medicine ,030217 neurology & neurosurgery ,Biotechnology - Abstract
The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the γ-globin genes HBG1 and HBG2 with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98-99% target modification, which is maintained when multiplexed across three loci. Delivered as messenger RNA, ABE8s induce no significant levels of single guide RNA (sgRNA)-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.
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- 2020
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34. Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL
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Caroline Diorio, Ryan Murray, Mark Naniong, Luis Barrera, Adam Camblin, John Chukinas, Lindsey Coholan, Aaron Edwards, Tori Fuller, Claudia Gonzales, Stephan A. Grupp, Alden Ladd, Melissa Le, Angelica Messana, Faith Musenge, Haley Newman, Yeh-Chuin Poh, Henry Poulin, Theresa Ryan, Rawan Shraim, Sarah K. Tasian, Tiffaney Vincent, Lauren Young, Yingying Zhang, Giuseppe Ciaramella, Jason Gehrke, and David T. Teachey
- Subjects
Gene Editing ,Cytosine ,Immunology ,Hematopoietic Stem Cell Transplantation ,Humans ,Cell Biology ,Hematology ,CRISPR-Cas Systems ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Biochemistry - Abstract
Allogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with between 90% and 99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using 4 simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation, or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitro and in vivo models. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells, with high potential for clinical translation for relapsed and refractory T-ALL.
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- 2022
35. Sekundarni sindrom nemirnih nogu
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Walker, Ryan Murray Alexander, Telarović, Srđana, Poljaković-Skurić, Zdravka, and Habek, Mario
- Abstract
Secondary restless legs syndrome is now considered one of the most common disorders you have never heard of. With a prevalence of around 5 to 15%, this disorder affects a significant portion of the population and therefore requires attention. The objective of this review was to look at all of the possible secondary causes of restless legs syndrome and whether there is strong enough evidence to support these associations. It is now widely accepted that the first depiction of possible RLS was outlined in 1672 by the well-known English Physician Sir Thomas Willis. Restless legs syndrome diagnoses has to meet the criteria set out by the international restless legs syndrome study group (IRLSSG). Restless legs syndrome can present in many various forms and can occur at any time throughout life. Patients who suffer from restless legs syndrome will often experience motor and sensory symptoms, or one of the two components. There are also other associated features such as sleep disturbances and fatigue, that can often negatively affect the quality of life of the sufferer. Restless legs syndrome can be treated with various nonpharmacological and pharmacological options. In this review we found a strong association between restless legs syndrome and iron deficiency, renal disease and pregnancy. Parkinson’s disease, essential tremor, some neuropathies and familial ataxias also showed some strong evidence towards an increase in the prevalence of restless legs syndrome in these disorders, however more long-term studies need to be done. We looked at many other possible associations, such as multiple sclerosis, myelinopathy, fibromyalgia and stroke. These, however, lack concrete findings to their associations, with possible alternative factors contributing to these associations with restless legs syndrome. It is important that restless legs syndrome sufferers be identified. Patients with mild symptoms, might simply need reassurance, while more moderate to severe symptoms might need pharmacological treatment. It is imperative that these secondary causes be screened when making the diagnosis of restless legs syndrome, as by treating them the symptoms of restless legs syndrome may be resolved and therefore not require other treatment modalities specific to restless legs syndrome., Pacijenti koji pate od sindroma nemirnih nogu često će imati motoričke i senzorne simptome, ili jednu od dvije komponente. Postoje i druge povezane značajke poput poremećaja spavanja i umora, koje često mogu negativno utjecati na kvalitetu života oboljelog. Sindrom nemirnih nogu može se liječiti raznim nefarmakološkim i farmakološkim mogućnostima. U ovom smo pregledu pronašli snažnu povezanost između sindroma nemirnih nogu i nedostatka željeza, bolesti bubrega i trudnoće. Parkinsonova bolest, esencijalni tremor, neke neuropatije i obiteljske ataksije također su pokazali neke snažne dokaze o Sekundarni sindrom nemirnih nogu sada se smatra jednim od najčešćih poremećaja za koji nikada niste čuli. S prevalencijom od oko 5 do 15%, ovaj poremećaj pogađa značajan dio populacije i zato zahtijeva pažnju. Cilj ovog pregleda bio je sagledati sve moguće sekundarne uzroke sindroma nemirnih nogu i postoje li dovoljno snažni dokazi koji podupiru ove asocijacije. Sada je široko prihvaćeno da je prvi prikaz mogućeg RLS-a izložio 1672. godine poznati engleski liječnik Sir Thomas Willis. Dijagnoze sindroma nemirnih nogu moraju udovoljavati kriterijima koje je postavila međunarodna istraživačka skupina za sindrom nemirnih nogu (IRLSSG). Sindrom nemirnih nogu može se pojaviti na mnogo različitih načina i može se javiti povećanju prevalencije sindroma nemirnih nogu kod ovih poremećaja, međutim potrebno je napraviti dugoročnija ispitivanja. Pregledali smo mnoge druge moguće povezanosti, poput multiple skleroze, mijelinopatije, fibromialgije i moždanog udara. Njima, međutim, nedostaju konkretni nalazi o njihovim udrugama, a mogući alternativni čimbenici doprinose tim udruženjima sa sindromom nemirnih nogu. Važno je identificirati oboljele od sindroma nemirnih nogu. Pacijentima s blagim simptomima možda će jednostavno trebati osiguranje, dok umjerenim do težim simptomima može biti potrebno farmakološko liječenje. Ove sekundarne uzroke morat će se pregledati prilikom postavljanja dijagnoze sindroma nemirnih nogu, jer se njihovim liječenjem simptomi sindroma nemirnih nogu mogu riješiti i stoga ne zahtijevaju druge modalitete liječenja specifične za sindrom nemirnih nogu.
- Published
- 2021
36. Realizing the Goals of the Advancing American Kidney Health Initiative: Toward a Better Future for Kidney Disease Research Funding
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Ryan Murray and Holly Kramer
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National Institutes of Health (U.S.) ,Nephrology ,Humans ,Kidney Diseases ,Kidney ,Medicare ,Goals ,United States ,Aged - Abstract
The Executive Order on Advancing American Kidney Health aimed to slow the progression of kidney disease, increase access to kidney transplantation, and expand home dialysis. In order to support the kidney health strategy laid out by the Advancing American Kidney Health, the National Institutes of Health, the National Institute of Diabetes, and Digestive, and Kidney Diseases, as well as other funding agencies must dedicate robust research funding to kidney disease. Currently, federal research investment for kidney health is less than 1% of Medicare fee-for-service expenditures for Americans with kidney disease. To address disparities in federal research funding, nephrology organizations are working together to advocate for increased federal commitment to kidney disease research. Underfunding of kidney disease research impedes scientific opportunities and innovation and prevents the collaboration of young investigators with research faculty that can accelerate the exodus of talent within the nephrology research workforce. This review provides an overview of the current state of federal research funding for kidney disease within the United States. In addition, we discuss ongoing advocacy efforts and programs that aim to increase federal funding for kidney-related research and accelerate the development of new and better therapies.
- Published
- 2021
37. Research Priorities for Kidney-Related Research-An Agenda to Advance Kidney Care: A Position Statement From the National Kidney Foundation
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Nora Franceschini, John Cijiang He, Erich P. Ditschman, Jonathan Himmelfarb, Ryan Murray, Holly Mattix Kramer, Deidra C. Crews, Joe Ix, Silvia Ferrè, Jennifer E. Flythe, Robert Friedman, Steve L. Seliger, János Peti-Peterdi, Troy Zimmerman, Anne Rohall-Andrade, Precious McCowan, Bessie A. Young, Sylvia E. Rosas, Kerry Willis, Bryan Kestenbaum, Nisha Bansal, Janine Reed, Arlene B. Chapman, John David Spencer, Jay L. Koyner, Joseph A. Vassalotti, Barry I. Freedman, Samir M. Parikh, Susan E. Quaggin, Benjamin D. Humphreys, Opeyemi A. Olabisi, Julie J. Scialla, Mary Baliker, Holly Kramer, Shuta Ishibe, Sharon Pearce, Orlando M. Gutiérrez, Kevin J. Fowler, Mark J. Sarnak, Peter C. Harris, Katalin Susztak, Matthew D. Breyer, Nichole Jefferson, Paul M. Palevsky, Joseph V. Bonventre, Ian H. de Boer, Eddie Siew, and Glenda V. Roberts
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Nephrology ,medicine.medical_specialty ,business.industry ,Research ,Psychological intervention ,Disease ,medicine.disease ,Kidney ,Health equity ,United States ,Clinical trial ,Clinical research ,Nursing ,Internal medicine ,Medicine ,Humans ,Diabetic Nephropathies ,Renal Insufficiency, Chronic ,business ,Kidney disease ,Pharmaceutical industry - Abstract
Despite the high prevalence and economic burden of chronic kidney disease (CKD) in the United States, federal funding for kidney-related research, prevention, and education activities under the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) remains substantially lower compared to other chronic diseases. More federal support is needed to promote critical research that will expand knowledge of kidney health and disease, develop new and effective therapies, and reduce health disparities. In 2021, the National Kidney Foundation (NKF) convened 2 Research Roundtables (preclinical and clinical research), comprising nephrology leaders from prominent US academic institutions and the pharmaceutical industry, key bodies with expertise in research, and including individuals with CKD and their caregivers and kidney donors. The goal of these roundtables was to identify priorities for preclinical and clinical kidney-related research. The research priorities identified by the Research Roundtables and presented in this position statement outline attainable opportunities for groundbreaking and critically needed innovations that will benefit patients with kidney disease in the next 5-10 years. Research priorities fall within 4 preclinical science themes (expand data science capability, define kidney disease mechanisms and utilize genetic tools to identify new therapeutic targets, develop better models of human disease, and test cell-specific drug delivery systems and utilize gene editing) and 3 clinical science themes (expand number and inclusivity of clinical trials, develop and test interventions to reduce health disparities, and support implementation science). These priorities in kidney-related research, if supported by additional funding by federal agencies, will increase our understanding of the development and progression of kidney disease among diverse populations, attract additional industry investment, and lead to new and more personalized treatments.
- Published
- 2021
38. Recognizing Posttraumatic Stress Disorder in Primary Care
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Ryan Murray, Jon Davine, Donald R. McCreary, Alexandra Heber, and James M. Thompson
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medicine.medical_specialty ,business.industry ,Addiction ,media_common.quotation_subject ,Chronic pain ,Physical health ,Stigma (botany) ,Primary care ,medicine.disease ,Posttraumatic stress ,medicine ,Screening tool ,Psychiatry ,business ,media_common ,Psychological trauma - Abstract
This chapter summarizes primary care principles for recognizing psychologically traumatized patients and engaging them in treatment. Psychological trauma is a psychiatric injury that occurs in response to severely stressful events and can become chronic if not treated. Trauma-informed clinicians understand how psychological trauma changes how people feel, think, and behave. Recognizing and engaging a psychologically traumatized patient for diagnosis and treatment is one of the most satisfying clinical experiences in primary care, opening doors for both patient and provider. While posttraumatic stress disorder (PTSD) is a common psychiatric disorder, the condition tends to be under-recognized. PTSD recognition is challenging owing to stigma, the variety of presentations, the non-specific nature, and range of severity of PTSD symptoms, and high co-occurrence with other conditions. Patients can be reluctant to seek care, disclose traumatizing events, or remember events. PTSD is more prevalent in people with addictions, chronic physical health conditions, chronic pain, medically unexplained symptoms, other psychiatric disorders, and occupations such as military and public safety personnel. Fourteen diverse case examples demonstrate some of the many faces of PTSD in adults. Barriers and facilitators to recognizing PTSD in primary care and targeted use of screening tools are discussed.
- Published
- 2021
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39. Local minimizers and slow motion for the mass preserving Allen–Cahn equation in higher dimensions
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Ryan Murray and Giovanni Leoni
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010101 applied mathematics ,Slow motion ,Applied Mathematics ,General Mathematics ,010102 general mathematics ,Mathematical analysis ,MathematicsofComputing_GENERAL ,Geometry ,0101 mathematics ,01 natural sciences ,Allen–Cahn equation ,Mathematics - Abstract
This paper completely resolves the asymptotic development of order 2 2 by Γ \Gamma -convergence of the mass-constrained Cahn–Hilliard functional. Important new results on the slow motion of interfaces for the mass preserving Allen–Cahn equation and the Cahn–Hilliard equations in higher dimension are obtained as an application.
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- 2019
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40. Kidney-Related Research in the United States: A Position Statement From the National Kidney Foundation and the American Society of Nephrology
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Sylvia E. Rosas, Ryan Murray, Troy Zimmerman, Holly Kramer, Anupam Agarwal, Paul M. Palevsky, and Susan E. Quaggin
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Nephrology ,medicine.medical_specialty ,Financing, Government ,Biomedical Research ,Population ,030232 urology & nephrology ,Hemodialysis, Home ,Population health ,Medicare ,Health Services Accessibility ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Internal medicine ,Environmental health ,Diabetes mellitus ,Research Support as Topic ,medicine ,Humans ,030212 general & internal medicine ,Obesity ,Healthcare Disparities ,Renal Insufficiency, Chronic ,education ,Societies, Medical ,education.field_of_study ,urogenital system ,business.industry ,Public health ,Health Policy ,Health Status Disparities ,medicine.disease ,Health equity ,United States ,Renal Replacement Therapy ,Socioeconomic Factors ,Kidney Failure, Chronic ,Public Health ,Health Expenditures ,business ,Kidney disease - Abstract
Kidney disease is an important US public health problem because it affects over 37 million Americans, and Medicare expenditures for patients with chronic kidney disease now alone exceed $130 billion annually. Kidney disease is characterized by strong racial, ethnic, and socioeconomic disparities, and reducing kidney disease incidence will positively impact US health disparities. Due to the aging of the US population and an unabated obesity epidemic, the number of patients receiving treatment for kidney failure is anticipated to increase, which will escalate kidney disease health expenditures. The historical and current investment in kidney-related research via the National Institute of Diabetes and Digestive and Kidney Diseases has severely lagged behind ongoing expenditures for kidney disease care. Increasing research investment will identify, develop, and increase implementation of interventions to slow kidney disease progression, reduce incidence of kidney failure, enhance survival, and improve quality of life. This perspective states the urgent reasons why increasing investment in kidney-related research is important for US public health. The National Kidney Foundation and the American Society of Nephrology are working together to advocate for increased funding for the National Institute of Diabetes and Digestive and Kidney Diseases. The long-term goal is to reduce the burden of kidney disease in the US population and improve the quality of life of patients living with kidney disease.
- Published
- 2021
41. Dropout Fails to Regularize Nonparametric Learners
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Ryan Murray and Ernest Fokoué
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Statistics and Probability ,Artificial neural network ,business.industry ,Computer Science::Neural and Evolutionary Computation ,Nonparametric statistics ,Astrophysics::Cosmology and Extragalactic Astrophysics ,Covering number ,Machine learning ,computer.software_genre ,Variety (cybernetics) ,Computer Science::Systems and Control ,Simple (abstract algebra) ,ComputingMilieux_COMPUTERSANDEDUCATION ,Artificial intelligence ,Limit (mathematics) ,Proxy (statistics) ,business ,computer ,Dropout (neural networks) ,Mathematics - Abstract
Dropout is a popular tool employed in training neural networks for learning tasks. In shallow networks, a variety of recent works have provided a theoretical understanding of the regularizing effect of dropout. The case of deeper networks is, up to this point, only partially understood from a theoretical standpoint. This work studies the theory of dropout from a nonparametric viewpoint, which is considered a proxy for the deepest layers of a neural network. Utilizing ideas from the calculus of variations, it is shown that in the nonparametric limit, the simplest version of dropout has no regularizing effect. Quantified covering number bounds are given describing the failure of dropout to regularize, and simple numerical illustrations are also given to explore the effect of dropout during a transition towards nonparametric settings.
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- 2021
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42. Distributed Gradient Flow: Nonsmoothness, Nonconvexity, and Saddle Point Evasion
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H. Vincent Poor, Brian Swenson, Ryan Murray, and Soummya Kar
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FOS: Computer and information sciences ,Linear programming ,Stable manifold theorem ,Stable manifold ,Computer Science Applications ,Control and Systems Engineering ,Optimization and Control (math.OC) ,Saddle point ,Convergence (routing) ,Trajectory ,FOS: Mathematics ,Applied mathematics ,Computer Science - Multiagent Systems ,Electrical and Electronic Engineering ,Balanced flow ,Gradient descent ,Mathematics - Optimization and Control ,Mathematics ,Multiagent Systems (cs.MA) - Abstract
The paper considers distributed gradient flow (DGF) for multi-agent nonconvex optimization. DGF is a continuous-time approximation of distributed gradient descent that is often easier to study than its discrete-time counterpart. The paper has two main contributions. First, the paper considers optimization of nonsmooth, nonconvex objective functions. It is shown that DGF converges to critical points in this setting. The paper then considers the problem of avoiding saddle points. It is shown that if agents' objective functions are assumed to be smooth and nonconvex, then DGF can only converge to a saddle point from a zero-measure set of initial conditions. To establish this result, the paper proves a stable manifold theorem for DGF, which is a fundamental contribution of independent interest. In a companion paper, analogous results are derived for discrete-time algorithms.
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- 2020
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43. Endobiont viruses sensed by the human host - beyond conventional antiparasitic therapy.
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Raina N Fichorova, Yujin Lee, Hidemi S Yamamoto, Yuko Takagi, Gary R Hayes, Russell P Goodman, Xenia Chepa-Lotrea, Olivia R Buck, Ryan Murray, Tomasz Kula, David H Beach, Bibhuti N Singh, and Max L Nibert
- Subjects
Medicine ,Science - Abstract
Wide-spread protozoan parasites carry endosymbiotic dsRNA viruses with uncharted implications to the human host. Among them, Trichomonas vaginalis, a parasite adapted to the human genitourinary tract, infects globally ∼250 million each year rendering them more susceptible to devastating pregnancy complications (especially preterm birth), HIV infection and HPV-related cancer. While first-line antibiotic treatment (metronidazole) commonly kills the protozoan pathogen, it fails to improve reproductive outcome. We show that endosymbiotic Trichomonasvirus, highly prevalent in T. vaginalis clinical isolates, is sensed by the human epithelial cells via Toll-like receptor 3, triggering Interferon Regulating Factor -3, interferon type I and proinflammatory cascades previously implicated in preterm birth and HIV-1 susceptibility. Metronidazole treatment amplified these proinflammatory responses. Thus, a new paradigm targeting the protozoan viruses along with the protozoan host may prevent trichomoniasis-attributable inflammatory sequelae.
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- 2012
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44. 155 CD5 knockout enhances the potency of multiplex base-edited allogeneic anti-CD5 CAR T-cell therapy for the treatment of T-cell malignancies
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Lauren Young, Ryan Murray, Scott Haskett, Yeh Chuin Poh, Yingying Zhang, David Sweezy, Lisa Schlehuber, Faith Musenge, Sarah E. Smith, Luis A. Barrera, Amanda Costa, Jason Michael Gehrke, Hui Wu, Adam Camblin, MarkVic Naniong, Yinmeng (Amy) Yang, Alden Ladd, Giuseppe Ciaramella, and Lindsey Coholan
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Pharmacology ,Cancer Research ,medicine.diagnostic_test ,business.industry ,Electroporation ,medicine.medical_treatment ,T cell ,Immunology ,Cell ,Flow cytometry ,medicine.anatomical_structure ,Cytokine ,Oncology ,Antigen ,In vivo ,medicine ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,CD5 ,business - Abstract
BackgroundT-cell lymphomas and leukemias are a class of diseases lacking durable effective therapies, where median survival for patients suffering from relapsed/refractory disease is often measured in months. Translation of B-cell targeting CAR-T therapeutic success to T-cell malignancies comes with significant challenges. Notably, the shared expression of target antigens on malignant T-cells and in the T-cell product itself results in CAR-T activation and fratricide during manufacturing. To overcome the challenges associated with creating CD5-targeting CAR-Ts, we developed a process to simultaneously base edit five target genes, including CD5 and PD1, to produce potency-enhanced allogeneic anti-CD5 CAR T-cells for use as an off-the-shelf treatment for T-cell malignancies.MethodsAnti-CD5 CAR-Ts were produced in a GMP-compatible process using T-cells isolated from healthy human donors. T-cells were modified using base editing technology to simultaneously knock-out five target genes in a single electroporation step. Edited T-cells were transduced with a lentivirus encoding a second-generation anti-CD5 CAR. Knockout frequencies were evaluated by flow cytometry and next-generation sequencing. Anti-CD5 CAR-Ts were then characterized for their specificity in vitro and potency in in vivo xenograft tumor models.ResultsSimultaneous base editing at five genomic loci resulted in anti-CD5 CAR-Ts edited with 94–98% efficiency at each target gene, greatly diminishing the likelihood of GvHD, CAR-T rejection, fratricide, and checkpoint inhibitor activation. In addition, CD5 has an established role as a negative regulator of TCR signaling, and T cells lacking CD5 have enhanced proliferative capacity.1 Anti-CD5 CAR T-cells with or without CD5 KO demonstrated equally potent cytotoxicity and cytokine production in vitro against CD5 expressing tumor lines. However, CD5 KO greatly improved in vivo efficacy of anti-CD5 CAR-Ts in a murine model of T-ALL against established tumor xenografts. Mice previously cleared of tumor underwent a second tumor challenge to assess the persistence of anti-CD5 CAR-T cells and were cleared of tumor a second time, indicating extended persistence of functional anti-CD5 CAR-T cells in vivo.ConclusionsOur approach addresses current technological limitations in developing and applying CAR-Ts that target T-cell malignancies and demonstrates that simultaneous multiplex base editing of up to five targets can create universally compatible, fratricide-resistant, therapeutically active anti-CD5 CAR-Ts. We further demonstrate that CD5 knockout produces CAR-T cells with enhanced potency capable of clearing multiple tumor challenges in vivo. We are progressing this CD5-targeting CAR-T cell product towards potential clinical development for the treatment of T cell malignancies and other CD5+ hematological tumors.ReferenceGuillaume V, Peredo G, Romain R. CD5, an Undercover Regulator of TCR Signaling. Frontiers in Immunology 2018;9:2900.Ethics ApprovalAll animal studies were performed according to the guidelines and approval of the Institutional Animal Care and Use Committee.
- Published
- 2021
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45. Cutoff estimates for the linearized Becker–Döring equations
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Robert L. Pego and Ryan Murray
- Subjects
010101 applied mathematics ,Physics ,Applied Mathematics ,General Mathematics ,Quantum electrodynamics ,010102 general mathematics ,Spectrum (functional analysis) ,Cutoff ,0101 mathematics ,01 natural sciences - Published
- 2017
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46. Modelling uncertainty in reinforcement learning
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Michele Palladino and Ryan Murray
- Subjects
Computer Science::Machine Learning ,Computer science ,business.industry ,Control (management) ,Reinforcement learning ,State (computer science) ,Artificial intelligence ,Markov decision process ,business ,Measure (mathematics) ,Thompson sampling - Abstract
This paper discusses the model problem presented in "A model for system uncertainty in reinforcement learning", Systems and Control Letters, 2018, for certain tasks in reinforcement learning. The model provides a framework to deal with situations in which the system dynamics is not known and encodes the available information about the state dynamics as a measure on the space of functions. Such a measure is updated in time, taking into account all the previous measurements of the state variable and extracting new information from them. Here we will mainly focus on the differences between the present model and central algorithms used in reinforcement learning (i.e. value iteration and Thompson sampling).
- Published
- 2019
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47. Directed evolution of adenine base editors with increased activity and therapeutic application
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Nicole M, Gaudelli, Dieter K, Lam, Holly A, Rees, Noris M, Solá-Esteves, Luis A, Barrera, David A, Born, Aaron, Edwards, Jason M, Gehrke, Seung-Joo, Lee, Alexander J, Liquori, Ryan, Murray, Michael S, Packer, Conrad, Rinaldi, Ian M, Slaymaker, Jonathan, Yen, Lauren E, Young, and Giuseppe, Ciaramella
- Subjects
Gene Editing ,Cytosine ,HEK293 Cells ,Adenosine Deaminase ,Adenine ,Mutation ,Humans ,DNA ,CRISPR-Cas Systems ,RNA, Guide, Kinetoplastida - Abstract
The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34
- Published
- 2019
48. Distributed Gradient Descent: Nonconvergence to Saddle Points and the Stable-Manifold Theorem
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Ryan Murray, H. Vincent Poor, Brian Swenson, and Soummya Kar
- Subjects
FOS: Computer and information sciences ,0209 industrial biotechnology ,Dynamical systems theory ,020206 networking & telecommunications ,Stable manifold theorem ,02 engineering and technology ,Stable manifold ,Maxima and minima ,020901 industrial engineering & automation ,Optimization and Control (math.OC) ,Saddle point ,Convergence (routing) ,FOS: Mathematics ,0202 electrical engineering, electronic engineering, information engineering ,Applied mathematics ,Computer Science - Multiagent Systems ,Almost surely ,Gradient descent ,Mathematics - Optimization and Control ,Multiagent Systems (cs.MA) ,Mathematics - Abstract
The paper studies a distributed gradient descent (DGD) process and considers the problem of showing that in nonconvex optimization problems, DGD typically converges to local minima rather than saddle points. The paper considers unconstrained minimization of a smooth objective function. In centralized settings, the problem of demonstrating nonconvergence to saddle points of gradient descent (and variants) is typically handled by way of the stable-manifold theorem from classical dynamical systems theory. However, the classical stable-manifold theorem is not applicable in distributed settings. The paper develops an appropriate stable-manifold theorem for DGD showing that convergence to saddle points may only occur from a low-dimensional stable manifold. Under appropriate assumptions (e.g., coercivity), this result implies that DGD typically converges to local minima and not to saddle points.
- Published
- 2019
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49. A maximum principle argument for the uniform convergence of graph Laplacian regressors
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Ryan Murray and Nicolás García Trillos
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FOS: Computer and information sciences ,Computer Science - Machine Learning ,Partial differential equation ,Uniform convergence ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,MathematicsofComputing_NUMERICALANALYSIS ,Machine Learning (stat.ML) ,Mathematics - Statistics Theory ,Statistics Theory (math.ST) ,Mathematics::Spectral Theory ,Nonparametric regression ,Machine Learning (cs.LG) ,Maximum principle ,Mathematics - Analysis of PDEs ,Statistics - Machine Learning ,FOS: Mathematics ,Graph (abstract data type) ,Applied mathematics ,Empirical risk minimization ,Laplacian matrix ,MathematicsofComputing_DISCRETEMATHEMATICS ,Mathematics ,Analysis of PDEs (math.AP) - Abstract
This paper investigates the use of methods from partial differential equations and the Calculus of variations to study learning problems that are regularized using graph Laplacians. Graph Laplacians are a powerful, flexible method for capturing local and global geometry in many classes of learning problems, and the techniques developed in this paper help to broaden the methodology of studying such problems. In particular, we develop the use of maximum principle arguments to establish asymptotic consistency guarantees within the context of noise corrupted, non-parametric regression with samples living on an unknown manifold embedded in $\mathbb{R}^d$. The maximum principle arguments provide a new technical tool which informs parameter selection by giving concrete error estimates in terms of various regularization parameters. A review of learning algorithms which utilize graph Laplacians, as well as previous developments in the use of differential equation and variational techniques to study those algorithms, is given. In addition, new connections are drawn between Laplacian methods and other machine learning techniques, such as kernel regression and k-nearest neighbor methods.
- Published
- 2019
50. Disability and compensation principles in military-to-civilian transition support
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Raun Lazier, Ryan Murray, and Mary Beth MacLean
- Subjects
Rehabilitation ,Guiding Principles ,business.industry ,Compensation (psychology) ,medicine.medical_treatment ,Best practice ,Context (language use) ,Public relations ,Subject-matter expert ,Political science ,Health care ,medicine ,Program Design Language ,business - Abstract
Before the end of World War Two, many nations had implemented entitlements for veterans, such as disability pensions, health care, and vocational rehabilitation. However, the concept of disability has evolved since then, and some nations have modernized disability compensation. We examined how disability is assessed, how compensation is structured, and modern principles in designing and reforming veteran disability compensation for 11 nations through a survey, interviews with subject matter experts, and a literature review. While there are some similarities in these schemes, substantial differences were found in the components of the schemes and the context in which they operate. This makes best practices difficult to identify and limits the application of certain aspects of program design to other nations. As a result, this chapter presents five key interrelated guiding principles in designing effective compensation systems: adequacy of compensation for losses; program affordability; integration of rehabilitation; simplicity; and comprehensiveness as well as a description of modern concepts of disability. This provided a framework for developing five recommendations that can help guide nations without compensation schemes in their development and to guide reforms among nations with existing schemes.
- Published
- 2019
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