Reading Human Genome

"We've provided a series of snapshots that shows how the genome is read one gene at a time," says biophysicist Eva Nogales who led this research. "For the genetic code to be transcribed into messenger RNA, the DNA double helix has to be opened and the strand of gene sequences has to be properly positioned so that RNA polymerase, the enzyme that catalyzes transcription, knows where the gene starts. The electron microscopy images we produced show how this is done."

Says Paula Flicker of the National Institutes of Health's National Institute of General Medical Sciences, which partly funded the research, "The process of transcription is essential to all living things so understanding how it initiates is enormously important. This work is a beautiful example of integrating multiple approaches to reveal the structure of a large molecular complex and provide insight into the molecular basis of a fundamental cellular process."

Nogales, who holds joint appointments with Berkeley Lab, the University of California (UC) at Berkeley, and the Howard Hughes Medical Institute (HHMI), is the corresponding author of a paper describing this study in the journalNature. The paper is titled "Structural visualization of key steps in human transcription initiation." Co-authors are Yuan He, Jie Fang and Dylan Taatjes.

The fundamental process of life by which information in the genome of a living cell is used to generate biomolecules that carry out cellular activities is the so-called "central dogma of molecular biology." It states that genetic information flows from DNA to RNA to proteins. This straightforward flow of information is initiated by an elaborate system of proteins that operate in a highly choreographed fashion with machine-like precision. Understanding how this protein machinery works in the context of passing genetic information from DNA to RNA (transcription) is a must for identifying malfunctions that can turn cells cancerous or lead to a host of other problems.

Berkeley Lab researchers have produced the first step-by-step snapshots of the assembly of transcription factors and RNA polymerase into a transcription pre-initiation complex. (Image courtesy of Nogales group)

Nogales and members of her research group used cryo-electron microscopy (cryo-EM), where protein samples are flash-frozen at liquid nitrogen temperatures to preserve their structure, to carry out in vitro studies of reconstituted and purified versions of the "transcription pre-initiation complex." This complex is a large assemblage of proteins composed of RNA polymerase II (Pol II) plus a class of proteins known as general transcription factors that includes the TATA-binding protein (TBP), TFIIA, TFIIB, TFIIF, TFIIE and TFIIH. All of the components in this complex work together to ensure the accurate loading of DNA into Pol II at the start of a gene sequence.

"There's been a lack of structural information on how the transcription pre-initiation complex complex is assembled, but with cryo-EM and our in vitro reconstituted system we've been able to provide pseudo-atomic models at various stages of transcription initiation that illuminate critical molecular interactions during this step-by-step process," Nogales says.

The in vitro reconstituted transcription pre-initiation complex was developed by Yuan He, lead author on the Nature paper and a post-doctoral student in Nogales's research group.

"This reconstituted system provided a model for the sequential assembly pathway of transcription initiation and was essential for us to get the most biochemically homogenous samples," Nogales says. "Also essential was our ability to use automated data collection and processing so that we could generate all our structures in a robust manner."

Among the new details revealed in the step-by-step cryo-EM images was how the transcription factor protein TFIIF engages Pol II and promoter DNA to stabilize both a closed DNA pre-initiation complex and an open DNA-promoter complex, and also how it regulates the selection of a transcription start-site.

"Comparing the closed versus open DNA states led us to propose a model that describes how DNA is moved during the process of promoter opening," says He. "Our studies provide insight into how THIIH uses ATP hydrolysis as a source of energy to actually open and push the DNA to the active site of Pol II."

Nogales and her colleagues plan to further investigate the process of DNA loading into Pol II, as well as to include additional transcription factors into the assembly that are required for regulation of gene expression.

"Our goal is to actually build a structural model of the entire -- more than two million daltons -- protein machinery that recognizes and regulates all human DNA promoters," Nogales says. "For now we have the structural framework that's been needed to integrate biochemical and structural data into a unified mechanistic understanding of transcription initiation."

This research was funded by the National Institute of General Medical Sciences and the National Cancer Institute under NIH grant numbers GM063072 and CA127364.

http://www.sciencedaily.com/releases/2013/02/130227151306.htm

MWC 2013 Spain

Alcatel One Touch, meanwhile, announced that it will be showing 13 (yes, 13) new smartphones at the show this year. That'll be an interesting hands on.

You're probably wondering where Samsung went. We're not sure either. There's no press conference scheduled, so the chance of seeing any big new phones is slim to none. If you're waiting for the Galaxy S IV, you're going to have to wait a bit longer—the latest rumors pit the announcement in March.

On the other hand, all signs point to Samsung introducing the Galaxy Note 8.0, an 8-inch version of the stylus-equipped Galaxy Note 10.1 we gave an Editors' Choice award to over the summer. On the Apple scale, 8 inches is pretty close in size to the 7.9-inch iPad mini.

http://www.pcmag.com/article2/0,2817,2415690,00.asp

Telemedicine

One of the main limitations of traditional microfluidic diagnostic devices is their reliance on an external reader for moving fluids and giving a result. External readers can be expensive, break easily, and be lost or stolen, rendering the diagnostic cards useless. Our patterned paper-based diagnostic technology platform was designed specifically to avoid these issues by automatically wicking fluid and producing a colorimetric result that can be interpreted by eye. While our platform allows us to create visually semi-quantitative diagnostics, such as our liver function test, sometimes a more quantitative result is preferred.

In order to provide a quantitative result without requiring an external reader, we are leveraging the rapid expansion of mobile phones in the developing world. Today’s mobile phones contain image capture and processing capabilities that match what would be needed by an external reader, and, as they are now widespread even in rural areas of the developing world, they can be enabled to give quantitative results without the need to purchase an external reader.

http://www.dfa.org/

MIT top 50 Companies

http://bit.ly/UKNK62

Semiconductor Review

The mathematical computations required to update the complete set of linear regression parameters embedded in the Cowan LRA forecasting model have been carried out.

The newly derived set of linear regression parameters reflect 29 years (1984 to 2012) of historical global semiconductor sales numbers as a basis of predicting future quarterly and full year sales and sale growth forecast expectations by exercising the Cowan LRA model. It will cross $300 B water mark.

Indian semiconductor industry in 2013

Earlier this year, I had the pleasure of keynoting ISA Vision Conference in India where I discussed the growing frustration within India over the country’s apparent delay in becoming a major player in the fabless sector of the semiconductor industry. The pressure will only become more intense as India’s consumption of electronics is predicted to exceed $400 billion by 2020.

“Fortunately, India has all the elements in place to cultivate a vibrant, growing fabless semiconductor industry. First, India enjoys worldwide leadership in high tech with some of the most influential design teams in the world. It is already a leading provider of design services and silicon IP, with the world’s third largest number of silicon IP companies headquartered in India. India also has one of the creative pools of engineering resources and educational institutions in the world, graduating the second highest number of university students per year in the world, with a growing number of them engineers.

“Recognizing the region is poised to become the next great fabless incubator, a growing number of angel investors, both in India and in the West, are eager to fund new companies in India. A particularly successful model has been fabless companies headquartered in the US with the majority of design, and the innovation, being done in India. Beceem was a good example (acquired by Broadcom in 2010 for $316 million).

“There is a fertile environment for creating multi-national fabless semiconductor companies in India. Remember, it takes time to establish and grow a new industry. Qualcomm, for example, started as a contract R&D services organization in 1985 and introduced its first IC product three years later. It spent the next 20 years revolutionizing the wireless communications industry, climbing up the list of top semiconductor companies. In fact, the average age for leading fabless and IP companies worldwide is over 20 years old.”

CEO, Mentor Graphics

Brain Pacemaker

Kathy is the first of up to 10 patients who will be enrolled in an FDA approved study at Ohio State's Wexner Medical Center to determine if using a brain pacemaker can improve cognitive and behavioral functioning in patients with Alzheimer's disease.

The study employs the use of deep brain stimulation (DBS), the same technology used to successfully treat about 100,000 patients worldwide with movement disorders such as Parkinson's disease. In the study, researchers hope to determine whether DBS surgery can improve function governed by the frontal lobe and neural networks involved in cognition and behavior by stimulating certain areas of the brain with a pacemaker.

Dr. Douglas Scharre, neurologist and director of the division of cognitive neurology, and Dr. Ali Rezai, neurosurgeon and director of the neuroscience program, both at Wexner Medical Center, are conducting the study.

"If the early findings that we're seeing continue to be robust and progressive, then I think that will be very promising and encouraging for us," says Rezai, who also directs the Center for Neuromodulation at Ohio State. "But so far we are cautiously optimistic."

The deep brain stimulation implant is similar to a cardiac pacemaker device with the exception that the pacemaker wires are implanted in the brain rather than the heart. "Basically, the pacemakers send tiny signals into the brain that regulate the abnormal activity of the brain and normalize it more," says Rezai. "Right now, from what we're seeing in our first patient, I think the results are encouraging, but this is research. We need to do more research and understand what's going on."

The study, which will enroll people with mild or early-stage Alzheimer's disease, will help determine if DBS has the potential to improve cognitive, behavioral and functional deficits.

Sanford continues to be evaluated to determine the effectiveness of the technology, says Rezai. She says she volunteered for the study to help others avoid the angst she has suffered as Alzheimer's slowly disrupted her life.

"I'm just trying to make the world a better place," says Sanford. "That's all I'm doing." Her father, Joe Jester, says he is proud that his daughter is participating in the study, and is pleased to see her showing improvements.

"This study seemed to just give us hope," said Jester. "I guess we were at the place where you just don't do anything and watch the condition deteriorate over the years, or try to do something that would give us hope and might stop the progression of this disease."

Alzheimer's disease is the most common form of degenerative dementia, afflicting about 5.5 million Americans and costing more than $100 billion per year, ranking it the third costliest disease in terms of health care expenditures in the United States.

Alzheimer's disease -- which has no cure and is not easily managed -- becomes progressively disabling with loss of memory, cognition, worsening behavioral function, in addition to a gradual loss of independent functioning, says Scharre.

The Alzheimer's study is scheduled to be completed in 2015

fMRI and ECoG

Six weeks before the implantation surgery, the team conducted functional magnetic resonance imaging (fMRI) of Mr. Hemmes' brain while he watched videos of arm movement. They used that information to place a postage stamp-size electrocortigraphy (ECoG) grid of 28 recording electrodes on the surface of the brain region that fMRI showed controlled right arm and hand movement. Wires from the device were tunneled under the skin of his neck to emerge from his chest where they could be connected to computer cables as necessary.

For 12 days at his home and nine days in the research lab, Mr. Hemmes began the testing protocol by watching a virtual arm move, which triggered neural signals that were sensed by the electrodes. Distinct signal patterns for particular observed movements were used to guide the up and down motion of a ball on a computer screen. Soon after mastering movement of the ball in two dimensions, namely up/down and right/left, he was able to also move it in/out with accuracy on a 3-dimensional display.

http://www.sciencedaily.com/releases/2013/02/130208124818.htm

GE to create Robots for Sterilizing Surgical Tools

GE to Create Robotic Hospital System to Assist with Sterilization

Posted: February 5, 2013 

As part of GE's automation system this robotic arm would be capable of picking up, placing, organizing, and accounting for the medical implements that go into surgical toolkits. (Photo: Business Wire)

In conjunction with General Electric (GE) Healthcare and the U.S. Department of Veteran's Affairs (VA), the GE Global Research group is commencing a two-year, $2.5 million project to develop a prototype robotic system that will be capable of locating, sorting, delivering, and sterilizing surgical tools. Using a combination of robotic systems, computer vision technology, and RFID tracking and identification, the system will function with little oversight and manage tools and medical devices for doctors.Once complete, the prototype system will be placed into a VA hospital where it will be able to perform kitting of surgical tools, sterilization functions, and even transport tools to and from the operating theater when needed while also ensuring they are sterile and in working order.

Lynn DeRose, principle investigator and auto-ID technology expert in the Distributed Intelligent Systems Lab at GE Global Research says that GE is hoping to combine technologies that have been used in industrial automated manufacturing processes for years with new artificial intelligence technologies to have a significant impact on hospital throughput, patient safety, and healthcare costs. “At GE, we’re uniquely positioned to construct a smart solution that can make operating rooms run more efficiently, save millions of dollars in healthcare costs and lead to better patient outcomes,” DeRose says. “According to experts in the field, the surgical operation and recovery setting is considered the fastest growing and most resource intensive section of the hospital, accounting for approximately 30 - 50% of a hospital’s budget. Simply put, the operating theater is the single largest contributor to a facility’s bottom line. Any gains in efficiency that lead to more revenue being generated will be felt in a big way.”  

Next Generation Sequencing

Mitochondrial DNA Disorder

Purpose:

The application of massively parallel sequencing technology to the analysis of the mitochondrial genome has demonstrated great improvement in the molecular diagnosis of mitochondrial DNA–related disorders. The objective of this study was to investigate the performance characteristics and to gain new insights into the analysis of the mitochondrial genome.

Methods:

The entire mitochondrial genome was analyzed as a single amplicon using a long-range PCR–based enrichment approach coupled with massively parallel sequencing. The interference of the nuclear mitochondrial DNA homologs was distinguished from the actual mitochondrial DNA sequences by comparison with the results obtained from conventional PCR–based Sanger sequencing using multiple pairs of primers.

Results:

Our results demonstrated the uniform coverage of the entire mitochondrial genome. Massively parallel sequencing of the single amplicon revealed the presence of single-nucleotide polymorphisms and nuclear homologs of mtDNA sequences that cause the erroneous and inaccurate variant calls when PCR/Sanger sequencing approach was used. This single amplicon massively parallel sequencing strategy provides an accurate quantification of mutation heteroplasmy as well as the detection and mapping of mitochondrial DNA deletions.

Conclusion:

The ability to quantitatively and qualitatively evaluate every single base of the entire mitochondrial genome is indispensible to the accurate molecular diagnosis and genetic counseling of mitochondrial DNA–related disorders. This new approach may be considered as first-line testing for comprehensive analysis of the mitochondrial genome.

Genet Med advance online publication 3 January 2013

Keywords:

 

long-range PCR; massively parallel sequencing; mitochondrial disorders; mitochondrial genome; mtDNA large deletions; nuclear mitochondrial DNA homologs (NUMTs)

It was previously believed that these mutations happened completely by chance, with no regard for their effects on the organisms. Recently, there have been studies suggesting that these mutations occur in response to environmental challenges. That is to say, they are more likely to occur when they are advantageous to the organism, rather than when they are neutral or disadvantageous. When cells were deprived of a certain amino acid, tryptophan, for prolonged periods of time, point mutations in trp operon reverted to tryptophan, leading to an advantageous result, more frequently than under normal conditions when the mutations were neutral. In addition, the tryptophan mutation rate was unaffected when the cells were deprived of another amino acid, cysteine, further suggesting that the mutation rate was specific to situations in which the mutation was advantageous.

[edit]

ERK1/2 Signaling Pathway

Nitric oxide inhibits the neuroprotective ERK1/2 signaling pathway

Learning and memory are in part controlled by NMDA-type glutamate receptors in the brain. These receptors are linked to pores in the nerve cell membrane that regulate the flow of calcium and sodium in and out of the nerve cells. When these NMDA receptors get over-activated, they trigger the production of nitric oxide. In turn, nitric oxide attaches to other proteins via a reaction called S-nitrosylation, which was first discovered by Lipton and colleagues. When those S-nitrosylated proteins are involved in cell survival and lifespan, nitric oxide can cause brain cells to die prematurely -- a hallmark of neurodegenerative disease.

http://www.sciencedaily.com/releases/2013/02/130204153910.htm

LTE Market

LTE Market

There is a rapidly growing demand for broadband-enabled data applications within certain vertical market segments including public safety, oil, gas and energy production, defense and others. Wireless infrastructure and support service providers are optimizing LTE as the technology of choice for general communications and various applications including remote data acquisition, video surveillance, multimedia PTT, and others for private LTE network deployments. Mind Commerce expects LTE services in these key vertical market segments to grow at a CAGR of nearly 63% and eventually account for nearly $23 Billion in service revenue by the end of 2018.This report provides an in depth assessment of LTE in industry verticals including use cases, case studies, business case, value chain analysis, adoption timelines, and evaluation of key trends and drivers. The report includes forecasts for subscriptions and service revenue for 2012 to 2018 with sub-market data for the following industries: Oil, Gas and Energy, Construction, Agriculture, Mining, Utilities, Transportation, Defense, Public Safety, Education and Distance Learning, Healthcare. Forecasts also include a breakdown by consumer and enterprise users.

http://bit.ly/UUJY98

Hospital Planning

http://bit.ly/WOclDj

Next Revolution

Jacobs said that Qualcomm's Snapdragon 800 Series is designed for the next generation of LTE-Advanced, and can support download rates up to 150 Mbps. The 800 will also integrate the latest 802.11ac WiFi, and increase the video capability to the UltraHD level for playback and recording, at 4X the resolution of 1080p.

www.eedailynews.com/2013/01/2013-international-consumer-electronics.html