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The eight-foot underwater touchscreen features specialized dolphin-friendly "apps" and a symbolic keyboard to provide the dolphins -- which are intelligent and highly social -- with opportunities to interact with the system. Credit: The Marine Mammal Communication and Cognition collaboration (m2c2.net). Using optical technology specifically developed for this project, dolphins at the National Aquarium in Baltimore, MD, are at the center of research from an interdisciplinary team from Hunter College and Rockefeller University. The system involves an underwater computer touchscreen through which dolphins are able to interact and make choices. The system, the first of its kind, will be used to investigate dolphin intelligence and communication by providing them choice and control over a number of activities. Researchers believe this technology will help extend the high-throughput revolution in biology that has brought us whole genome sequencing and the BRAIN project, into the field of animal cognition. The eight-foot underwater touchscreen features specialized dolphin-friendly "apps" and a symbolic keyboard to provide the dolphins—which are intelligent and highly social—with opportunities to interact with the system. To make the system safe for the dolphins, the touchscreen has been installed outside an underwater viewing window, so that no parts of the device are in the pool: the animals' touch is detected purely optically. While the research is still in its early stages, the team has embarked on studies aimed at understanding dolphin vocal learning and communication, their capacity for symbolic communication, and what patterns of behavior may emerge when the animals have the ability to request items, videos, interactions and images. The interdisciplinary research team is comprised of Diana Reiss, a dolphin cognition and communication research scientist and Professor in the Department of Psychology at Hunter College; biophysicist Marcelo Magnasco, Professor and Head of the Laboratory of Integrative Neuroscience at Rockefeller University; Ana Hocevar, a postdoctoral research scientist; and Sean Woodward, a doctoral student, both in Magnasco's lab. "We hope this technologically-sophisticated touchscreen will be enriching for the dolphins and also enrich our science by opening a window into the dolphin mind," says Reiss. "Giving dolphins increased choice and control allows them to show us reflections of their way of thinking and may help us decode their vocal communication." Reiss is known for her earlier work demonstrating "mirror self-recognition" in dolphins (and elephants) as well as a prior dolphin study that pioneered the use of an interactive underwater keyboard system and demonstrated their capacity for spontaneous vocal imitation and self-organized learning. "It was surprisingly difficult to find an elegant solution that was absolutely safe for the dolphins, but it has been incredibly rewarding to work with these amazing creatures and see their reactions to our system," says Magnasco. "It has always been hard to keep up with dolphins, they are so smart; a fully interactive and programmable system will help us follow them in any direction they take us." "The interactive system was designed to engage the dolphins without requiring explicit training. It is an open system in which the dolphins' use of the touchscreen will shape how the system evolves," says Hocevar, who built the hardware and programmed its functionality. In addition to the touchscreen itself, the dolphin's habitat at the National Aquarium has been outfitted with equipment to record their behavior and vocalizations as they encounter and begin to use the technology. "We want to monitor whether the dolphins integrate novel elements from touchpad interactions, such as acoustical signals, into their daily repertoire, to which end we have installed an array of underwater microphones and video cameras," says Woodward. Already, the scientists have begun to introduce the dolphins to some of the system's interactive apps, so the animals can explore on their own how touching the screen results in specific contingencies. "Without any explicit training or encouragement from us, one of the younger dolphins, Foster, spontaneously showed immediate interest and expertise in playing a dolphin version of Whack-a-Mole," Reiss says, "in which he tracks and touches moving fish on the touchscreen." This research is funded by The National Science Foundation, The Eric and Wendy Schmidt Fund for Strategic Innovation, and a fellowship from the Raymond and Beverly Sackler Foundation, and it is carried out in partnership with the National Aquarium. "Using methods from statistical physics to analyze dolphin communication will open the door to understand how other animals communicate, which could be a game-changer in understanding how even human language originated," said Krastan Blagoev, the program director for the National Science Foundation's Physics of Living Systems program, which funded the research. "Projects like this not only enable science, but excite the next generation to think about science." The research team hopes that the information gleaned from this research will also result in increased empathy toward dolphins and inspire global policies for their protection.


News Article | May 25, 2017
Site: www.eurekalert.org

Using optical technology specifically developed for this project, dolphins at the National Aquarium in Baltimore, MD, are at the center of research from an interdisciplinary team from Hunter College and Rockefeller University. The system involves an underwater computer touchscreen through which dolphins are able to interact and make choices. The system, the first of its kind, will be used to investigate dolphin intelligence and communication by providing them choice and control over a number of activities. Researchers believe this technology will help extend the high-throughput revolution in biology that has brought us whole genome sequencing and the BRAIN project, into the field of animal cognition. The eight-foot underwater touchscreen features specialized dolphin-friendly "apps" and a symbolic keyboard to provide the dolphins--which are intelligent and highly social--with opportunities to interact with the system. To make the system safe for the dolphins, the touchscreen has been installed outside an underwater viewing window, so that no parts of the device are in the pool: the animals' touch is detected purely optically. While the research is still in its early stages, the team has embarked on studies aimed at understanding dolphin vocal learning and communication, their capacity for symbolic communication, and what patterns of behavior may emerge when the animals have the ability to request items, videos, interactions and images. The interdisciplinary research team is comprised of Diana Reiss, a dolphin cognition and communication research scientist and Professor in the Department of Psychology at Hunter College; biophysicist Marcelo Magnasco, Professor and Head of the Laboratory of Integrative Neuroscience at Rockefeller University; Ana Hocevar, a postdoctoral research scientist; and Sean Woodward, a doctoral student, both in Magnasco's lab. "We hope this technologically-sophisticated touchscreen will be enriching for the dolphins and also enrich our science by opening a window into the dolphin mind," says Reiss. "Giving dolphins increased choice and control allows them to show us reflections of their way of thinking and may help us decode their vocal communication." Reiss is known for her earlier work demonstrating "mirror self-recognition" in dolphins (and elephants) as well as a prior dolphin study that pioneered the use of an interactive underwater keyboard system and demonstrated their capacity for spontaneous vocal imitation and self-organized learning. "It was surprisingly difficult to find an elegant solution that was absolutely safe for the dolphins, but it has been incredibly rewarding to work with these amazing creatures and see their reactions to our system," says Magnasco. "It has always been hard to keep up with dolphins, they are so smart; a fully interactive and programmable system will help us follow them in any direction they take us." "The interactive system was designed to engage the dolphins without requiring explicit training. It is an open system in which the dolphins' use of the touchscreen will shape how the system evolves," says Hocevar, who built the hardware and programmed its functionality. In addition to the touchscreen itself, the dolphin's habitat at the National Aquarium has been outfitted with equipment to record their behavior and vocalizations as they encounter and begin to use the technology. "We want to monitor whether the dolphins integrate novel elements from touchpad interactions, such as acoustical signals, into their daily repertoire, to which end we have installed an array of underwater microphones and video cameras," says Woodward. Already, the scientists have begun to introduce the dolphins to some of the system's interactive apps, so the animals can explore on their own how touching the screen results in specific contingencies. "Without any explicit training or encouragement from us, one of the younger dolphins, Foster, spontaneously showed immediate interest and expertise in playing a dolphin version of Whack-a-Mole," Reiss says, "in which he tracks and touches moving fish on the touchscreen." This research is funded by The National Science Foundation, The Eric and Wendy Schmidt Fund for Strategic Innovation, and a fellowship from the Raymond and Beverly Sackler Foundation, and it is carried out in partnership with the National Aquarium. "Using methods from statistical physics to analyze dolphin communication will open the door to understand how other animals communicate, which could be a game-changer in understanding how even human language originated," said Krastan Blagoev, the program director for the National Science Foundation's Physics of Living Systems program, which funded the research. "Projects like this not only enable science, but excite the next generation to think about science." The research team hopes that the information gleaned from this research will also result in increased empathy toward dolphins and inspire global policies for their protection. The Rockefeller University is the world's leading biomedical research university and is dedicated to conducting innovative, high-quality research to improve the understanding of life for the benefit of humanity. Our 82 laboratories conduct research in neuroscience, immunology, biochemistry, genomics, and many other areas, and a community of 1,800 faculty, students, postdocs, technicians, clinicians, and administrative personnel work on our 14-acre Manhattan campus. Our unique approach to science has led to some of the world's most revolutionary and transformative contributions to biology and medicine. During Rockefeller's 115-year history, 24 of our scientists have won Nobel Prizes, 22 have won Albert Lasker Medical Research Awards, and 20 have garnered the National Medal of Science, the highest science award given by the United States. Hunter College, located in the heart of Manhattan, is the largest college in the City University of New York (CUNY) system. Founded in 1870, it is also one of the oldest public colleges in the country and famous for the diversity of its student body, which is as diverse as New York City itself. Most Hunter students are the first in their families to attend college and many go on to top professional and graduate programs, winning Fulbright scholarships, Mellon fellowships, National Institutes of Health grants, and other competitive honors. More than 23,000 students currently attend Hunter, pursuing undergraduate and graduate degrees in more than 170 areas of study. The 1,700 full- and part-time members of Hunter's faculty are unparalleled. They receive prestigious national grants, contribute to the world's leading academic journals, and play major roles in cutting-edge research. They are fighting cancer, formulating public policy, expanding our culture, enhancing technology, and more.


Tang L.H.,Sloan Kettering Cancer Center | Contractor T.,Raymond and Beverly Sackler Foundation | Clausen R.,Raymond and Beverly Sackler Foundation | Klimstra D.S.,Sloan Kettering Cancer Center | And 7 more authors.
Clinical Cancer Research | Year: 2012

Purpose: In mice, genetic changes that inactivate the retinoblastoma tumor suppressor pathway often result in pancreatic neuroendocrine tumors (Pan-NETs). Conversely, in humans with this disease, mutations in genes of the retinoblastoma pathway have rarely been detected, even in genome-wide sequencing studies. In this study, we took a closer look at the role of the retinoblastoma pathway in human Pan-NETs. Experimental Design: Pan-NET tumors from 92 patients were subjected to immunohistochemical staining for markers of the retinoblastoma pathway. To search for amplifications of retinoblastoma pathway genes, genomic DNAs from 26 tumors were subjected to copy number analysis. Finally, a small-molecule activator of the retinoblastoma pathway was tested for effects on the growth of two Pan-NET cell lines. Results: A majority of tumors expressed high amounts of Cdk4 or its partner protein cyclin D1. High amounts of phosphorylated Rb1 were present in tumors that expressed high levels of Cdk4 or cyclin D1. The copy numbers of Cdk4 or the analogous kinase gene Cdk6 were increased in 19% of the tumors. Growth of the human Pan-NET cell line QGP1 was inhibited in a xenograft mouse model by the Cdk4/6 inhibitor, PD 0332991, which reactivates the retinoblastoma pathway. Conclusions: Inactivation of the retinoblastoma pathway was indicated for most Pan-NETs. Gene amplification and overexpression of Cdk4 and Cdk6 suggests that patients with Pan-NETs may respond strongly to Cdk4/6 inhibitors that are entering clinical trials. ©2012 AACR.


Wong C.,Raymond and Beverly Sackler Foundation | Vosburgh E.,Raymond and Beverly Sackler Foundation | Vosburgh E.,Rutgers University | Levine A.J.,Rutgers University | And 4 more authors.
Journal of Visualized Experiments | Year: 2012

Neuroendocrine tumors (NETs) are rare tumors, with an incidence of two per 100, 000 individuals per year, and they account for 0.5% of all human malignancies. 1 Other than surgery for the minority of patients who present with localized disease, there is little or no survival benefit of systemic therapy. Therefore, there is a great need to better understand the biology of NETs, and in particular define new therapeutic targets for patients with nonresectable or metastatic neuroendocrine tumors. 3D cell culture is becoming a popular method for drug screening due to its relevance in modeling the in vivo tumor tissue organization and microenvironment. 2,3 The 3D multicellular spheroids could provide valuable information in a more timely and less expensive manner than directly proceeding from 2D cell culture experiments to animal (murine) models. To facilitate the discovery of new therapeutics for NET patients, we have developed an in vitro 3D multicellular spheroids model using the human NET cell lines. The NET cells are plated in a non-adhesive agarose-coated 24-well plate and incubated under physiological conditions (5% CO 2, 37 °C) with a very slow agitation for 16-24 hr after plating. The cells form multicellular spheroids starting on the 3 rd or 4 th day. The spheroids become more spherical by the 6 th day, at which point the drug treatments are initiated. The efficacy of the drug treatments on the NET spheroids is monitored based on the morphology, shape and size of the spheroids with a phase-contrast light microscope. The size of the spheroids is estimated automatically using a custom-developed MATLAB program based on an active contour algorithm. Further, we demonstrate a simple method to process the HistoGel embedding on these 3D spheroids, allowing the use of standard histological and immunohistochemical techniques. This is the first report on generating 3D spheroids using NET cell lines to examine the effect of therapeutic drugs. We have also performed histology on these 3D spheroids, and displayed an example of a single drug's effect on growth and proliferation of the NET spheroids. Our results support that the NET spheroids are valuable for further studies of NET biology and drug development. © 2012 Journal of Visualized Experiments.


Chen W.,Rutgers University | Wong C.,Raymond and Beverly Sackler Foundation | Wong C.,Rutgers University | Vosburgh E.,Raymond and Beverly Sackler Foundation | And 6 more authors.
Journal of Visualized Experiments | Year: 2014

The increasing number of applications of three-dimensional (3D) tumor spheroids as an in vitro model for drug discovery requires their adaptation to large-scale screening formats in every step of a drug screen, including large-scale image analysis. Currently there is no ready-to-use and free image analysis software to meet this large-scale format. Most existing methods involve manually drawing the length and width of the imaged 3D spheroids, which is a tedious and time-consuming process. This study presents a high-throughput image analysis software application - SpheroidSizer, which measures the major and minor axial length of the imaged 3D tumor spheroids automatically and accurately; calculates the volume of each individual 3D tumor spheroid; then outputs the results in two different forms in spreadsheets for easy manipulations in the subsequent data analysis. The main advantage of this software is its powerful image analysis application that is adapted for large numbers of images. It provides high-throughput computation and quality-control workflow. The estimated time to process 1,000 images is about 15 min on a minimally configured laptop, or around 1 min on a multi-core performance workstation. The graphical user interface (GUI) is also designed for easy quality control, and users can manually override the computer results. The key method used in this software is adapted from the active contour algorithm, also known as Snakes, which is especially suitable for images with uneven illumination and noisy background that often plagues automated imaging processing in high-throughput screens. The complimentary "Manual Initialize" and "Hand Draw" tools provide the flexibility to SpheroidSizer in dealing with various types of spheroids and diverse quality images. This high-throughput image analysis software remarkably reduces labor and speeds up the analysis process. Implementing this software is beneficial for 3D tumor spheroids to become a routine in vitro model for drug screens in industry and academia.


Kim D.-W.,University of Virginia | Wu N.,Fred Hutchinson Cancer Research Center | Kim Y.-C.,H. Lee Moffitt Cancer Center and Research Institute | Cheng P.F.,Fred Hutchinson Cancer Research Center | And 13 more authors.
Genes and Development | Year: 2016

Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumorforming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer. © 2016 Napoli and Flores.


Francis J.M.,Cambridge Broad Institute | Francis J.M.,Dana-Farber Cancer Institute | Kiezun A.,Cambridge Broad Institute | Ramos A.H.,Cambridge Broad Institute | And 54 more authors.
Nature Genetics | Year: 2013

The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome-and genome-sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs. © 2013 Nature America, Inc.

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