Researchers define precise EEG Signature of Anesthesia-Induced Unconsciousness

More than 60,000 patients in the United States undergo general anesthesia for surgery every day. Currently, doctors use indirect measures of the brain state, such as heart rate and blood pressure, along with drug pharmacokinetics, pharmacodynamics and exhaled anesthetic gas typically are converted to a simple index score to indicate if a patient is adequately anesthetized during surgery. These indices are neither entirely reliable nor very informative. Inadequately administered anesthesia can result in intraoperative awareness and post-operative delirium. Drs. Emery N. Brown and Patrick L. Purdon, former NIH Director’s Pioneer Awardee and current NIH Director’s New Innovator Awardee, respectively, have studied brain activity during propofol-induced anesthesia using electroencephalogram (EEG) technology, which measures scalp electrical potentials, to better understand the mechanism of unconsciousness and to establish a direct method of tracking the transition between consciousness and unconsciousness during general anesthesia. In this study, the researchers gradually administered and reduced the anesthesia drug propofol in patients, while monitoring brain activity and behavioral loss of consciousness by asking patients to respond to auditory stimuli. This gradual induction and emergence from anesthesia allowed the researchers to precisely define an EEG brain signature, as well as behavioral markers that are associated with consciousness, unconsciousness, and the transition between these two states in patients undergoing propofol-induced general anesthesia. This research has provided a deeper understanding of the mechanism of propofol-induced loss of consciousness, and could be used to determine the EEG brain signatures of other anesthetics. Additionally, these results could be used to develop more direct and reliable methods for monitoring brain states of patients undergoing general anesthesia and could lead to new insights into the tailoring of drug dosage in real-time.

Reference:

P. L. Purdon et al., Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proceedings of the National Academy of Sciences, (March 4, 2013, 2013).

SUCCESS WITH GENE CIRCUITS COULD LEAD TO NEW APPROACHES TO GENE THERAPY

A gene circuit refers to the complex mechanism by which genetic material, encoded by DNA, interacts with proteins resulting in a specific phenotype, or an observable characteristic. This can be more readily understood by imagining an electrical circuit, where you can turn a light switch on or off to produce an observable characteristic of light or darkness, respectively. Gene circuits can be turned on or off just like a switch, thus the expression of the associated phenotype can therefore be turned off or on. Additionally, these circuits can be expressed as more than just on or off. Imagine a light switch with a dimming function by which the light can be expressed at different intensities. Similarly, these gene circuits can be regulated in order to express at different intensities rather than just on or off, in order to produce phenotypic differences at varying levels of expression. In nature, multiple genes in multiple gene circuits of a cell interact to regulate major biological processes like cell signaling or division. Researchers can construct simple synthetic gene circuits in order to study the expression of specific genes in living systems, such as microorganisms, as well as to create novel biological functions for practical applications.

NIH Director’s New Innovator Awardee, Gábor Balázsi, and colleagues have described a new method where they developed and optimized a synthetic gene circuit in yeast and were able to adapt the gene circuit to mammalian cells. Importantly, the authors optimized this gene circuit allowing them to finely adjust gene expression in a linear fashion with uniform gene expression across the entire cell population. Previously, scientists had been unable to directly transfer gene circuits developed in microorganisms directly into mammalian systems, such as human cells. Dr. Balázsi’s new findings will allow researchers to design circuits that can be tested and characterized in microorganisms, such as yeast, which are easier to engineer than mammalian cells, and then introduce the circuits into mammalian cells, a model more similar and representative to study the complexities of human disease. These gene circuits can be used to study the effects of specific gene expression on biological functions such as development, immune response, and nervous system response, and can be used to develop precisely controlled gene expression systems for use in individualized gene therapy to treat specific diseases and genetic conditions.

Reference:

D. Nevozhay, T. Zal, G. Balazsi, Transferring a synthetic gene circuit from yeast to mammalian cells. Nature communications 4, 1451 (Feb 5, 2013).

NEW MODEL ALLOWS SCIENTISTS TO STUDY MECHANISM OF HCM DEVELOPMENT AND TEST DRUGS FOR TREATMENT

Hypertrophic Cardiomyopathy (HCM) is a prevalent heart condition that involves the thickening of the heart walls, which overtime can lead to the development of an irregular heart beat and sudden cardiac death. HCM has been estimated to be the most common inherited heart condition in the world, and has been associated with several DNA mutations affecting sarcomeres, or the basic unit of a muscle.

Dr. Joseph Wu, an NIH Director’s New Innovator Award Recipient from Stanford University, and his colleagues, have developed a new technology using induced pluripotent stem cells (iPSCs) obtained from skin cells of a family of patients that allows them to model HCM at the level of a single cell. The researchers were able to turn the skin-derived iPSCs into heart muscle cells, permitting them to investigate the underlying causes of HCM development without requiring the difficult direct collection of diseased heart tissue. This model allowed the researchers to better understand how a specific DNA mutation, carried by affected members of this particular family, can lead to the development of HCM, and helped them to test therapies that might be used to treat or prevent HCM due to this specific mutation. This new technology can be used by other researchers to investigate the effect of other DNA mutations on the development of HCM, and to screen the effectiveness of new treatments and preventative therapies specific to each mutation.

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Reference:

Lan F, Lee AS, Liang P, Sanchez-Freire V, Nguyen PK, Wang L, Han L, Yen M, Wang Y, Sun N, Abilez OJ, Hu S, Ebert AD, Navarrete EG, Simmons CS, Wheeler M, Pruitt B, Lewis R, Yamaguchi Y, Ashley EA, Bers DM, Robbins RC, Longaker MT, Wu JC. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013 Jan 3;12(1):101-13. PubMed PMID: 23290139.

Self Assembling DNA Bricks

Dr Peng Yin and Dr. William Shih, both awardees of the Common Fund NIH Director’s New Innovator Award program, have described a new method to construct complex three dimensional structures by using short synthetic DNA strands which the investigators call “DNA bricks.” In this paper, the investigators used 32-nucleotide DNA strands which self-assembled into prescribed 3D structures without scaffolds. Each DNA brick can bind up to four local neighbors, and in a manner similar to Lego® bricks can be used to build complicated structures. This self assembly has allowed the investigators to create over 100 distinct structures which can be found here. This method may have a large variety of applications such as to develop smart drug delivery particles or provide a better way for nano-scale fabrication of inorganic materials.

Reference:

Yonggang Ke, Luvena Ong, William Shih, Peng Yin Three-Dimensional Structures Self-Assembled from DNA Bricks, Science - 30 November 2012 (Vol 338, pp1177-1183)

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More information describing the self assembly process can be found in the two videos below:

Video 1 Animated video containing narration which describes how 3D structures of DNA bricks are assembled.

Video 2 Animated video which depicts the nanofabrication technique called “DNA-brick self-assembly” using short synthetic strands of DNA that work like interlocking Lego® bricks.

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Stress-Amplifying Protein Linked to Diabetes

Dr. Feroz Papa, an associate professor of medicine at the University of California San Francisco and NIH Director’s Transformative Research Award recipient discovers a molecule amplifying stress in the earliest stages of diabetes.

Tele-medical Device Wins Top Honors

Dr. Aydogan Ozcan, an NIH Director’s New Innovator Award recipient, and colleagues at the University of California, Los Angeles (UCLA) garner first place in The Scientist magazine, “Top Ten Innovations of 2011” competition by developing a cell phone camera attachment that functions as a mobile microscope.

The device known as LUCAS (Lensless, Ultra-wide-field Cell monitoring Array platform based on Shadow imaging), is a light-weight holographic microscope that uses inexpensive off-the-shelf parts as an attachment to a cell phone’s camera. Biospeciman samples are loaded into the slide attachment of the device, and then battery operated light emitting diodes (LEDs) are used to illuminate the specimen and produce an image of the cells shadows. The image is then remastered using an algorithm remotely run from a computer. Although the resolution of the LUCAS is at the submicrometer level, the microscope can be used for wide-field imaging.

The technology coupled with the use of a cell phone provides a plethora of opportunities to capture and electronically transport biospeciman images in real time. The device can be used for water quality testing and even to monitor diseases such as Malaria. At the estimated cost of approximately 10 USD for the LUCAS attachment, the technology has the potential of providing diagnostic services to resource limited areas across the nation. Field tests around the world are already being planned for the LUCAS in 2012.

Reference:

Mudanyali O, Tseng D, Oh C, Isikman SO, Sencan I, Bishara W, Oztoprak C, Seo S, Khademhosseini B, Ozcan A. Compact, Light-weight and Cost-effective Microscope based on Lensless Incoherent Holography for Telemedicine Applications, 2010.June10. PMCID: PMC2902728

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• Read more about the New Innovator Award Program program...