Date:
August 13, 2014

 

Source:
Potsdam Institute for Climate Impact Research (PIK)

 

Summary:
Ice discharge from Antarctica could contribute up to 37 centimeters to the global sea level rise within this century, a new study shows. For the first time, an international team of scientists provide a comprehensive estimate on the full range of Antarctica’s potential contribution to global sea level rise based on physical computer simulations. The study combines a whole set of state-of-the-art climate models and observational data with various ice models.

 

 

20140815-1
Antarctica: In the future, more ice could break of and melt, researchers say.
Credit: PIK/Winkelmann

 

 

ce discharge from Antarctica could contribute up to 37 centimeters to the global sea level rise within this century, a new study shows. For the first time, an international team of scientists provide a comprehensive estimate on the full range of Antarctica’s potential contribution to global sea level rise based on physical computer simulations. Led by the Potsdam Institute for Climate Impact Research, the study combines a whole set of state-of-the-art climate models and observational data with various ice models. The results reproduce Antarctica’s recent contribution to sea level rise as observed by satellites in the last two decades and show that the ice continent could become the largest contributor to sea level rise much sooner than previously thought.

“If greenhouse gases continue to rise as before, ice discharge from Antarctica could raise the global ocean by an additional 1 to 37 centimeters in this century already,” says lead author Anders Levermann. “Now this is a big range — which is exactly why we call it a risk: Science needs to be clear about the uncertainty, so that decision makers at the coast and in coastal megacities like Shanghai or New York can consider the potential implications in their planning processes,” says Levermann.

Antarctica currently contributes less than 10 percent to global sea level rise

The scientists analyzed how rising global mean temperatures resulted in a warming of the ocean around Antarctica, thus influencing the melting of the Antarctic ice shelves. While Antarctica currently contributes less than 10 percent to global sea level rise and is a minor contributor compared to the thermal expansion of the warming oceans and melting mountain glaciers, it is Greenland and especially the Antarctic ice sheets with their huge volume of ice that are expected to be the major contributors to future long-term sea level rise. The marine ice sheets in West Antarctica alone have the potential to elevate sea level by several meters — over several centuries.

According to the study, the computed projections for this century’s sea level contribution are significantly higher than the latest IPCC projections on the upper end. Even in a scenario of strict climate policies limiting global warming in line with the 2°C target, the contribution of Antarctica to global sea level rise covers a range of 0 to 23 centimeters.

A critical input to future projections

“Rising sea level is widely regarded as a current and ongoing result of climate change that directly affects hundreds of millions of coastal dwellers around the world and indirectly affects billions more that share its financial costs,” says co-author Robert Bindschadler from the NASA Goddard Space Flight Center. “This paper is a critical input to projections of possible future contributions of diminishing ice sheets to sea level by a rigorous consideration of uncertainty of not only the results of ice sheet models themselves but also the climate and ocean forcing driving the ice sheet models. Billions of Dollars, Euros, Yuan etc. are at stake and wise and cost-effective decision makers require this type of useful information from the scientific experts.”

While the study signifies an important step towards a better understanding of Antarctica in a changing climate and its influence on sea level change within the 21st century, major modeling challenges still remain: Datasets of Antarctic bedrock topography, for instance, are still inadequate and some physical processes of interaction between ice and ocean cannot be sufficiently simulated yet.

Notably, the study’s results are limited to this century only, while all 19 of the used comprehensive climate models indicate that the impacts of atmospheric warming on Antarctic ice shelf cavities will hit with a time delay of several decades. “Earlier research indicated that Antarctica would become important in the long term,” says Levermann. “But pulling together all the evidence it seems that Antarctica could become the dominant cause of sea level rise much sooner.”


Story Source:

The above story is based on materials provided by Potsdam Institute for Climate Impact Research (PIK)Note: Materials may be edited for content and length.


Journal Reference:

  1. A. Levermann, R. Winkelmann, S. Nowicki, J. L. Fastook, K. Frieler, R. Greve, H. H. Hellmer, M. A. Martin, M. Meinshausen, M. Mengel, A. J. Payne, D. Pollard, T. Sato, R. Timmermann, W. L. Wang, R. A. Bindschadler. Projecting Antarctic ice discharge using response functions from SeaRISE ice-sheet modelsEarth System Dynamics, 2014; 5 (2): 271 DOI: 10.5194/esd-5-271-2014

 

Potsdam Institute for Climate Impact Research (PIK). “Antarctica’s ice discharge could raise sea level faster than previously thought.” ScienceDaily. ScienceDaily, 13 August 2014. <www.sciencedaily.com/releases/2014/08/140813182259.htm>.

 

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Date:
August 13, 2014

 

Source:
NIH/National Institute of Allergy and Infectious Diseases

 

Summary:
Scientists are pursuing injections or intravenous infusions of broadly neutralizing HIV antibodies (bNAbs) as a strategy for preventing HIV infection. This technique, called passive immunization, has been shown to protect monkeys from a monkey form of HIV called simian human immunodeficiency virus, or SHIV. To make passive immunization a widely feasible HIV prevention option for people, scientists want to modify bNAbs such that a modest amount of them is needed only once every few months.

 

 

Scientists are pursuing injections or intravenous infusions of broadly neutralizing HIV antibodies (bNAbs) as a strategy for preventing HIV infection. This technique, called passive immunization, has been shown to protect monkeys from a monkey form of HIV called simian human immunodeficiency virus, or SHIV. To make passive immunization a widely feasible HIV prevention option for people, scientists want to modify bNAbs such that a modest amount of them is needed only once every few months.

To that end, an NIH-led team of scientists has mutated the powerful anti-HIV bNAb called VRC01 so that, once infused into monkeys, it lasts three times longer in blood than unmutated VRC01, collects in rectal mucosal tissue, and persists there more than twice as long as unmutated VRC01. Concentrating anti-HIV bNAbs at mucosal surfaces of the rectum and vagina, the subject of additional study, is critical for blocking sexual transmission of HIV.

In addition, the scientists found, a low-dose infusion of mutated VRC01 protected monkeys against SHIV infection more effectively than a low-dose infusion of unmutated VRC01.

The mutation works by enhancing VRC01′s ability to bind to a cellular protein that prevents the antibody from degrading inside cells and influences how frequently the antibody reaches mucosal surfaces and stays there, the researchers report. This finding may inform antibody-based prevention strategies against not only HIV but also other viruses that invade the body at mucosal surfaces, including rotavirus, poliovirus, norovirus and influenza virus.

Next, the researchers will test infusions of mutated VRC01 in people to learn if it concentrates in mucosal tissues and persists there and in blood for an extended period.


Story Source:

The above story is based on materials provided by NIH/National Institute of Allergy and Infectious DiseasesNote: Materials may be edited for content and length.


Journal Reference:

  1. Sung-Youl Ko, Amarendra Pegu, Rebecca S. Rudicell, Zhi-yong Yang, M. Gordon Joyce, Xuejun Chen, Keyun Wang, Saran Bao, Thomas D. Kraemer, Timo Rath, Ming Zeng, Stephen D. Schmidt, John-Paul Todd, Scott R. Penzak, Kevin O. Saunders, Martha C. Nason, Ashley T. Haase, Srinivas S. Rao, Richard S. Blumberg, John R. Mascola, Gary J. Nabel. Enhanced neonatal Fc receptor function improves protection against primate SHIV infectionNature, 2014; DOI: 10.1038/nature13612

 

 

NIH/National Institute of Allergy and Infectious Diseases. “Scientists boost potential of passive immunization against HIV.” ScienceDaily. ScienceDaily, 13 August 2014. <www.sciencedaily.com/releases/2014/08/140813132118.htm>.

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Date:
August 11, 2014

 

Source:
Potsdam Institute for Climate Impact Research (PIK)

 

Summary:
Weather extremes in the summer — such as the record heat wave in the United States that hit corn farmers and worsened wildfires in 2012 — have reached an exceptional number in the last ten years. Human-made global warming can explain a gradual increase in periods of severe heat, but the observed change in the magnitude and duration of some events is not so easily explained.

 

 

20140813-1
Credit: © meryll / Fotolia

 

Weather extremes in the summer — such as the record heat wave in the United States that hit corn farmers and worsened wildfires in 2012 — have reached an exceptional number in the last ten years. Human-made global warming can explain a gradual increase in periods of severe heat, but the observed change in the magnitude and duration of some events is not so easily explained.
It has been linked to a recently discovered mechanism: the trapping of giant waves in the atmosphere. A new data analysis now shows that such wave-trapping events are indeed on the rise.

“The large number of recent high-impact extreme weather events has struck and puzzled us,” says Dim Coumou, lead author of the study conducted by a team of scientists from the Potsdam Institute for Climate Impact Research (PIK). “Of course we are warming our atmosphere by emitting CO2 from fossil fuels, but the increase in devastating heat waves in regions like Europe or the US seems disproportionate.” One reason could be changes in circulation patterns in the atmosphere. By analysing large sets of global weather data, the researchers found an intriguing connection.

Rossby Waves: meandering airstreams

An important part of the global air motion in the mid-latitudes normally takes the form of waves wandering around the globe, called Rossby Waves. When they swing north, they suck warm air from the tropics to Europe, Russia, or the US; and when they swing south, they do the same thing with cold air from the Arctic. However, the study shows that in periods with extreme weather, some of these waves become virtually stalled and greatly amplified. While a few warm days have little impact, effects on people and ecosystems can be severe when these periods are prolonged.

“Behind this, there is a subtle resonance mechanism that traps waves in the mid-latitudes and amplifies them strongly,” says Stefan Rahmstorf, co-author of the study to be published in the Proceedings of the US National Academy of Sciences (PNAS). Using advanced data analysis, the new study shows that when certain resonance conditions are fulfilled, the atmosphere tends to develop anomalously slowly propagating waves with large amplitudes, typically associated with extreme weather on the ground. An important finding is that this phenomenon is occurring more often: After the year 2000, it has been almost twice as frequent as before. “Evidence for actual changes in planetary wave activity was so far not clear. But by knowing what patterns to look for, we have now found strong evidence for an increase in these resonance events.”

The Arctic factor: warming twice as fast as most other regions

Why would these events be on the rise? Both theory and the new data suggest a link to processes in the Arctic. Since the year 2000, the Arctic is warming about twice as fast as the rest of the globe. One reason for this is that because the white sea ice is rapidly shrinking, less sunlight gets reflected back into space, while the open ocean is dark and hence warms more. “This melting of ice and snow is actually due to our lifestyle of churning out unprecedented amounts of greenhouse gases from fossil fuels,” says Hans Joachim Schellnhuber, co-author of the study and director of PIK. As the Arctic warms more rapidly, the temperature difference to other regions decreases. Yet temperature differences are a major driver of the atmospheric circulation patterns that in turn rule our weather.

“The planetary waves topic illustrates how delicately interlinked components in the Earth system are.” Schellnhuber concludes: “And it shows how disproportionately the system might react to our perturbations.”


Story Source:

The above story is based on materials provided by Potsdam Institute for Climate Impact Research (PIK)Note: Materials may be edited for content and length.


Journal Reference:

  1. Dim Coumou, Vladimir Petoukhov, Stefan Rahmstorf, Stefan Petri, and Hans Joachim Schellnhuber. Quasi-resonant circulation regimes and hemispheric synchronization of extreme weather in boreal summerPNAS, August 11, 2014 DOI: 10.1073/pnas.1412797111

 

Potsdam Institute for Climate Impact Research (PIK). “Trapped atmospheric waves triggering more weather extremes: Trend expected to continue.” ScienceDaily. ScienceDaily, 11 August 2014. <www.sciencedaily.com/releases/2014/08/140811170106.htm>.

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Date:
August 11, 2014

 

Source:
Brown University

 

Summary:
Biologists have worked with the Lambda virus as a model system for more than 50 years but they’ve never had an overarching picture of the molecular machines that allow it to insert or remove DNA from the cells that it infects. Now they can, thanks to an advance that highlights the intriguingly intricate way the virus accomplishes its genetic manipulations.

 

 

20140812-1
Lambda uses this DNA-protein complex to insert its DNA into that of its E.coli host. Another complex, or machine, extracts the DNA later.
Credit: Arthur Landy et al./Brown University

 

For half a century biologists have studied the way that the lambda virus parks DNA in the chromosome of a host E. coli bacterium and later extracts it as a model reaction of genetic recombination. But for all that time, they could never produce an overall depiction of the protein-DNA machines that carry out the work. In a pair of back-to-back papers in theProceedings of the National Academy of Sciences, scientists produce those long-sought renderings and describe how they figured out how they should look.

For people already in the know, here’s the advance in a sentence: The team of researchers at Brown University and the University of Pennsylvania mapped the specific ways that the recombination proteins in the machines bridge separate sites along the DNA of the host and the virus. But for everyone else, to understand what that means is to appreciate the evolved “ingenuity” of the lambda virus that has made it the subject of 50 years of intriguing study. Thankfully Lambda is benign, although it has medically nasty cousins that work much the same way.

Lambda, said co-corresponding author and Brown emeritus biology Professor Arthur Landy, is not one of those devil-may-care viruses that just smashes and grabs a host cell for immediate reproduction. Instead it senses the physiology of its E. coli host and waits for the cell to be healthy before striking, perhaps several generations of cell division later. To execute this more refined strategy it assembles a n ensemble of proteins, or a ” machine” to insert its DNA in a precise location in the DNA of the host (to ensure that its DNA will persist for many generations of host cells), and another machine to extract the DNA when the chosen moment of ideal host health arrives.

“The viruses make a ‘decision’ when they infect a cell as to whether or not this is a good time to lyse the cell and make more virus or whether it would be more propitious to integrate their chromosome into the E. coli chromosome, turn off their genes and sit there for generations,” Landy said. “Then when things look good again they use a different but related pathway to excise their chromosome, in order to make more virus and kill the cell.”

The way Lambda senses the health status of the host is built right into the machines. The machines incorporate key DNA-bending proteins that are made by E. coli to regulate expression of its own genes. Therefore the levels of these proteins also reflect the physiological state of the cell, Landy said. While some recombination proteins bind to just one site in each DNA, Lambda and its ilk go through the trouble of latching on to two distant sites in the DNA. The reason is to make the whole reaction depend on the presence of these key DNA-bending proteins to bend the sites into closer proximity. Without those proteins, the machines can’t work.

“”It makes the system gratuitously dependent on the proteins of the cell which serve as reporters of how well the cell is doing and where it is in its life cycle,” Landy said. “This makes it exquisitely sensitive to the physiology of the cell.”

Mapping Bridges

Biologists already knew all this, but they had never quite figured out how the recombination proteins in the machines bridge the two DNA sites,(i.e.,which sites were bound or bridged by the same recombination protein). Therefore they couldn’t really figure out what the whole machines looked like. Direct imaging tools such as crystallography never worked on the whole machines because it has too many forms, Landy said, and nuclear magnetic resonance never worked because it was too hard to make enough of the machines in a high enough concentration.

So the team did a couple of other experiments to figure out the bridging. One used chemicals and the other used genetics, but in each case they were essentially tagging different pairs of locations on the proteins and the DNA to see if any of those pairs, upon being connected, would produce a tell-tale effect: in the case of the chemistry the tell-tale was a change in the structural properties of the complex; in the case of the genetics it was a successful integration or excision reaction

It’s a bit like trying to wire a battery into a light bulb circuit where there are many pairs of loose wires, but only two that actually connect to the bulb. When one finally connects (or “bridges”) the right two loose wires with the battery’s electrodes, the light bulb lights and then one has mapped where those correct two wires are.

They combined their new mappings, including distance measurements within the protein-DNA complexes using fluorescent tags, with all of the other biochemical and structural information biologists have learned over the last 50 years, into a computer model to render the overall depictions of the machines.

They confirmed in further research that the models they generated explained and agreed with much of the observed behavior of the machines.

So now, long after they began to understand how worthwhile the Lambda virus was to study, researchers can finally see what these model DNA insertion and removal machines look like. That information will serve to make Lambda an even more powerful model for research and teaching, Landy said.


Story Source:

The above story is based on materials provided by Brown UniversityNote: Materials may be edited for content and length.


Journal Reference:

  1. Wenjun Tong, David Warren, Nicole E. Seah, Gurunathan Laxmikanthan, Gregory D. Van Duyne, and Arthur Landy. Mapping the {lambda} Integrase bridges in the nucleoprotein Holliday junction intermediates of viral integrative and excisive recombinationPNAS, August 2014 DOI: 10.1073/pnas.1413007111

 

Brown University. “Elusive viral ‘machine’ architecture finally rendered.” ScienceDaily. ScienceDaily, 11 August 2014. <www.sciencedaily.com/releases/2014/08/140811170153.htm>.

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To our friends and colleagues, ON TARGET is taking a short vacation to recharge some batteries and will be back after Labor Day (US). As we leave, we would like to share 2 recent highlights: one is the recognition in the August 2014 issue of PharmaVOICE, of Dr. Jules Mitchel, President of Target Health, as one of the 100 top inspirational and motivational individuals in the pharmaceutical industry in the category of entrepreneurs; the other is that Dean Gittleman, Sr. Director of Operations will be presenting on the topic of how to “Achieve eSource Data Compliance and Minimize the Need for Paper.“at the eSource Data in Clinical Investigations meeting in Philadelphia this month.


PharmaVOICE - Jules Mitchel, President of Target Health Designated as One of the 100 Top Inspirational and Motivational Individuals in the Pharmaceutical Industry in the Category of Entrepreneurs

PharmaVOICE Magazine has announced the 2014 PharmaVOICE 100 and Inaugural Red Jacket Award. Target Health is very pleased that Dr. Jules Mitchel, President of Target Health, has been designated as one of the 100 top inspirational and motivational individuals in the pharmaceutical industry in the category of entrepreneurs. The article can be found In The News section on our website (www.targethealth.com), and the entire edition of can be found on the PharmaVoice website (http://www.pharmavoice.com/content/digitaledition.html?pg=76).

 

20140811-1

 

eSource Meeting

 

Dean Gittleman, Sr. Director of Operations at Target Health will be presenting at CBI’s eSource Data in Clinical Investigations Forum, taking place August 20-21 in Philadelphia. Dean will speak on how to “Achieve eSource Data Compliance and Minimize the Need for Paper.“ The conference will provide industry case studies and applications of eSource data. Attendees will obtain insights into strategies for eliminating unnecessary duplication of data, ways to reduce transcription errors and pathways for real-time review of trial data. Attendees will be able to move beyond theory and hear practical applications and implementation strategies from industry pioneers as we as an industry collectively make the FDA-recommended shift toward the more efficient and reliable eSource Data. If you Register by 12 August 2014, you can save $500 off the the registration fee as a valued colleague of Target Health. Mention promo code ESRCTH when registering.

 

Speakers from pharma include:

 

1. AstraZeneca Pharmaceuticals (Raj Bandaru)

2. Bayer Healthcare (Johann Proeve)

3. BioMarin Pharmaceutical Inc. (Debra Lounsbury)

4. CSL Behring (Susmita Gupta)

5. Eisai Inc. (Peggy Siemon-Hryczyk)

6. Novartis Pharmaceuticals Corporation (Samar Noor)

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

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Date:
August 7, 2014

 

Source:
University of California – San Diego

 

Summary:
Scientists have reported that neurons derived from human induced pluripotent stem cells and grafted into rats after a spinal cord injury produced cells with 10s of thousands of axons extending virtually the entire length of the animals’ central nervous system.

 

20140808-1
This image depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.
Credit: UC San Diego School of Medicine

 

 

Building upon previous research, scientists at the University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.

Writing in the August 7 early online edition of Neuron, lead scientist Paul Lu, PhD, of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses.

The iPSCs used were developed from a healthy 86-year-old human male.

“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.

For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.

While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.

“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame — months to years — or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”

In the latest work, Lu, Tuszynski and colleagues converted skin cells from a healthy 86-year-old man into iPSCs, which possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons in collaboration with the laboratory of Larry Goldstein, PhD, director of the UC San Diego Sanford Stem Cell Clinical Center. The new human neurons were subsequently embedded in a matrix containing growth factors and grafted into two-week-old spinal cord injuries in rats.

Three months later, researchers examined the post-transplantation injury sites. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords, even extending into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. The transplants produced no detectable tumors.

While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. However, Lu noted that tests assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit. Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. Continuing research seeks to optimize transplantation methods to eliminate scar formation.

Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.

“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”


Story Source:

The above story is based on materials provided by University of California – San Diego. The original article was written by Scott LaFee and Jackie Carr. Note: Materials may be edited for content and length.


Journal Reference:

  1. Lu et al. Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells After Spinal Cord InjuryNeuron, 2014 (in press)

 

 

University of California – San Diego. “Dramatic growth of grafted stem cells in rat spinal cord.” ScienceDaily. ScienceDaily, 7 August 2014. <www.sciencedaily.com/releases/2014/08/140807121719.htm>.

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Date:
August 6, 2014

 

Source:
Massachusetts Institute of Technology

 

Summary:
A new gene-editing technique allows scientists to more rapidly study the role of mutations in tumor development. “The sequencing of human tumors has revealed hundreds of oncogenes and tumor suppressor genes in different combinations. The flexibility of this technology, as delivery gets better in the future, will give you a way to pretty rapidly test those combinations,” explained an author of the paper.

 

 

Sequencing the genomes of tumor cells has revealed thousands of mutations associated with cancer. One way to discover the role of these mutations is to breed a strain of mice that carry the genetic flaw — but breeding such mice is an expensive, time-consuming process.

Now, MIT researchers have found an alternative: They have shown that a gene-editing system called CRISPR can introduce cancer-causing mutations into the livers of adult mice, enabling scientists to screen these mutations much more quickly.

In a study appearing in the Aug. 6 issue of Nature, the researchers generated liver tumors in adult mice by disrupting the tumor suppressor genes p53 and pten. They are now working on ways to deliver the necessary CRISPR components to other organs, allowing them to investigate mutations found in other types of cancer.

“The sequencing of human tumors has revealed hundreds of oncogenes and tumor suppressor genes in different combinations. The flexibility of this technology, as delivery gets better in the future, will give you a way to pretty rapidly test those combinations,” says Institute Professor Phillip Sharp, an author of the paper.

Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the David H. Koch Professor of Biology, is the paper’s senior author. The lead authors are Koch Institute postdocs Wen Xue, Sidi Chen, and Hao Yin.

Gene disruption

CRISPR relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have copied this bacterial system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.

In some cases, the researchers simply snip out part of a gene to disrupt its function; in others, they also introduce a DNA template strand that encodes a new sequence to replace the deleted DNA.

To investigate the potential usefulness of CRISPR for creating mouse models of cancer, the researchers first used it to knock out p53 and pten, which protect cells from becoming cancerous by regulating cell growth. Previous studies have shown that genetically engineered mice with mutations in both of those genes will develop cancer within a few months.

Studies of such genetically engineered mice have yielded many important discoveries, but the process, which requires introducing mutations into embryonic stem cells, can take more than a year and costs hundreds of thousands of dollars. “It’s a very long process, and the more genes you’re working with, the longer and more complicated it becomes,” Jacks says.

Using Cas enzymes targeted to cut snippets of p53 and pten, the researchers were able to disrupt those two genes in about 3 percent of liver cells, enough to produce liver tumors within three months.

Many models possible

The researchers also used CRISPR to create a mouse model with an oncogene called beta catenin, which makes cells more likely to become cancerous if additional mutations occur later on. To create this model, the researchers had to cut out the normal version of the gene and replace it with an overactive form, which was successful in about 0.5 percent of hepatocytes (the cells that make up most of the liver).

The ability to not only delete genes, but also to replace them with altered versions “really opens up all sorts of new possibilities when you think about the kinds of genes that you would want to mutate in the future,” Jacks says. “Both loss of function and gain of function are possible.”

Using CRISPR to generate tumors should allow scientists to more rapidly study how different genetic mutations interact to produce cancers, as well as the effects of potential drugs on tumors with a specific genetic profile.

“This is a game-changer for the production of engineered strains of human cancer,” says Ronald DePinho, director of the University of Texas MD Anderson Cancer Center, who was not part of the research team. “CRISPR/Cas9 offers the ability to totally ablate gene function in adult mice. Enhanced potential of this powerful technology will be realized with improved delivery methods, the testing of CRISPR/Cas9 efficiency in other organs and tissues, and the use of CRISPR/Cas9 in tumor-prone backgrounds.”

In this study, the researchers delivered the genes necessary for CRISPR through injections into veins in the tails of the mice. While this is an effective way to get genetic material to the liver, it would not work for other organs of interest. However, nanoparticles and other delivery methods now being developed for DNA and RNA could prove more effective in targeting other organs, Sharp says.


Story Source:

The above story is based on materials provided by Massachusetts Institute of Technology. The original article was written by Anne Trafton. Note: Materials may be edited for content and length.


Journal Reference:

  1. Wen Xue, Sidi Chen, Hao Yin, Tuomas Tammela, Thales Papagiannakopoulos, Nikhil S. Joshi, Wenxin Cai, Gillian Yang, Roderick Bronson, Denise G. Crowley, Feng Zhang, Daniel G. Anderson, Phillip A. Sharp, Tyler Jacks. CRISPR-mediated direct mutation of cancer genes in the mouse liverNature, 2014; DOI:10.1038/nature13589

 

Massachusetts Institute of Technology. “Gene-editing technique offers new way to model cancer.” ScienceDaily. ScienceDaily, 6 August 2014. <www.sciencedaily.com/releases/2014/08/140806142213.htm>

 

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Promotions at Target Health

 

MR. YONG JOONG KIM has been promoted to Executive Director at Target Health. Yong Joong has been a key member of the Target Health team since May 1999. Yong Joong will continue to run the Data Management Department and work closely with Joonhyuk Choi, Leigh Ren and Glen Park to support their department’s activities. Yong Joong will also be a key member of the newly established Executive Committee at Target Health which includes Dean Gittleman, Glen Park, Mark Horn, Joyce Hays and Jules Mitchel. The Executive committee will help guide the growth of Target Health as we champion the “paperless“ clinical trial.“

 

MR. JOONHYUK CHOI, who joined our company in July 2001, has been promoted to Sr. Director, Software Development. Joonhyuk will have the software programmers, testers and IT reporting directly to him. Joonhyuk will be responsible for the development of new software products at Target Health as well as all operations requiring programming and support for Target Health’s software products.

 

View From Greensboro, North Carolina

 

Our friend and colleague, James Farley, Clinical Data Manager at TransTech Pharma LLC and subscriber to ON TARGET newsletter, is sharing some wildlife from Greensboro, NC. He tells us that “Believe it or not, the Green Heron lives at a pond which is in walking distance of our TransTech office!

 

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Green Heron, Greensboro, NC ©JFarleyPhotography.com

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchelor Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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Ebola Virus

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Electron micrograph of an Ebola virus virion

 

“The single biggest threat to man’s continued dominance on this planet is the virus,“ the Nobel Prize-winning biologist Joshua Lederberg once wrote. “There is no bomb, no poison, no plan of attack with the potential to do as much damage.“

 

Ebola virus disease (EVD) or Ebola hemorrhagic fever (EHF) one of the most dreaded human diseases, is caused by the ebola virus. Symptoms typically start two days to three weeks after contracting the virus, with a fever, throat and muscle pains, and headaches. Following the first symptoms, there is typically, nausea, vomiting, and diarrhea, along with decreased functioning of the liver and 1) ___. At this point, some people begin to have problems with bleeding. The disease is usually acquired when a person comes into contact with the blood or bodily 2) ___ of an infected animal such as a monkey or fruit bat. Fruit bats are believed to carry and spread the virus without being affected by it. Once infection of a human occurs, the disease may be spread from one person to another. Survivors may be able to transmit the disease via their semen for nearly two months. To make the diagnosis, typically other diseases with similar symptoms such as malaria, cholera and other viral hemorrhagic fevers are first excluded. The blood may then be tested for 3) ___ to the virus, or the viral RNA, or the virus itself, to confirm the diagnosis.

 

Prevention includes decreasing the spread of the disease from infected monkeys and pigs to humans. This may be done by checking these types of animals for infection and killing and properly disposing of the bodies, if the disease is discovered. Properly cooking meat and wearing protective clothing when handling meat may also be helpful, as is wearing protective clothing and washing 4) ___ when around a person who has the disease. Samples of bodily fluids and tissues from people with the disease should be handled with special caution. There is no specific treatment for the virus. Efforts to help persons who are infected include giving them either oral rehydration therapy or intravenous fluids. The disease has a high mortality rate: often between 50% and 90% of those who are infected with the virus. It typically occurs in outbreaks in tropical regions of Sub-Saharan Africa. Between 1976, when it was first identified, and 2014, fewer than 1,000 people a year have been infected. The largest outbreak to date is the ongoing 2014 West Africa Ebola outbreak, which is affecting Guinea, Sierra Leone, and Liberia. The disease was first identified in the Sudan and the Democratic Republic of the Congo. Efforts are ongoing to develop a vaccine; however, none exists as of 2014.

 

Manifestation of Ebola begins abruptly with a sudden onset of an influenza-like stage. Respiratory tract involvement is characterized by pharyngitis with sore throat, cough, dyspnea, and hiccups. The central nervous system is affected by the development of severe headaches, agitation, confusion, fatigue, seizures, and sometimes coma. Cutaneous presentation may include: maculopapular rash, petechiae, purpura, ecchymoses, and hematomas (especially around needle injection sites). In general, development of hemorrhagic symptoms is indicative of a negative 5) ___. However, contrary to popular belief, hemorrhage does not lead to hypovolemia (decreased blood volume) and is not the cause of death (total blood loss is low except during labor). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension, disseminated intravascular coagulation, and focal tissue necroses. The average time between contracting the infection and the onset of symptoms is 13 days, but can be as long as 25 days.

 

 

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Bushmeat being prepared for cooking in Ghana, 2013. Human consumption of equatorial animals in Africa in the form of bushmeat has been linked to the transmission of diseases to people, including Ebola.

 

The natural maintenance hosts of ebola viruses are unidentified. Primary infection may not necessarily be preventable in nature. Fruit bats are thought to be the natural hosts, as well as other wild animals. Thus, to avoid EVD, risk factors such as contact with bats, nonhuman primates, and 6) ___ meat should be avoided.

 

 

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The cytosol is a crowded solution of many different types of molecules that fills much of the volume of cells. The cytosol or intracellular fluid (ICF) or cytoplasmic matrix is the liquid found inside cells. It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments.

 

The ebola virus life cycle begins with virion attachment to specific cell-surface receptors, followed by fusion of the virion envelope with cellular membranes and the concomitant release of the virus nucleocapsid into the cytosol. Endothelial cells, mononuclear phagocytes, and hepatocytes are the main targets of infection. After infection, a secreted glycoprotein (sGP) known as the Ebola virus glycoprotein (GP) is synthesized. Ebola replication overwhelms protein synthesis of infected cells and host immune defenses. The GP forms a trimeric complex, which binds the virus to the endothelial cells lining the interior surface of blood vessels. The sGP forms adimeric protein that interferes with the signaling of neutrophils, a type of 7) ___ blood cell, which allows the virus to evade the immune system by inhibiting early steps of neutrophil activation.

 

These white blood cells also serve as carriers to transport the virus throughout the entire body to places such as the lymph nodes, liver, lungs, and spleen. The presence of viral particles and cell damage resulting from budding causes the release of cytokines, which are the signaling molecules for fever and inflammation. The cytopathic effect, from infection in the endothelial cells, results in a loss of vascular integrity. This loss in vascular integrity is furthered with synthesis of GP, which reduces specific integrins responsible for cell adhesion to the inter-cellular structure, and damage to the liver, which leads to coagulopathy.

 

One ray of hope, for the management of this terrible disease, is the knowledge that, Niemann-Pick C1 (NPC1) appears to be essential for Ebola infection. Two independent studies reported in the same issue of Nature showed that Ebola virus cell entry and replication requires the cholesterol transporter protein NPC1. When cells from Niemann-Pick disease, type C1 patients (who have a mutated form of NPC1) were exposed to Ebola virus in the laboratory, the cells survived and appeared immune to the virus, further indicating that Ebola relies on NPC1 to enter cells. This might imply that 8) ___ mutations in the NPC1 gene in humans could make some people resistant to one of the deadliest known viruses affecting humans. The same studies described similar results with Ebola’s cousin in the filovirus group, Marburg virus, showing that it too needs NPC1 to enter cells. Furthermore, NPC1 was shown to be critical to filovirus entry because it mediates infection by binding directly to the viral envelope glycoprotein. A later study confirmed these findings, and also showed that the second lysosomal domain of NPC1 mediates this binding. In one of the original studies, a small molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1. In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus. Together, these studies suggest NPC1 may be potential therapeutic target for an Ebola anti-viral drug.

 

Because Ebola 9) ___ are highly infectious as well as contagious, governments and individuals respond quickly to quarantine the outbreak areas; while the lack of roads and transportation in many parts of Africa helps to contain the outbreak of the disease. Airline crews are trained to spot the symptoms of Ebola in passengers flying from places where the virus is found. Crews are told to quarantine anyone who looks infected. During the summer of 2014, some international airlines have already halted flights to and from affected areas in Africa.

 

No Ebola virus-specific treatment exists. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration. Administration of anticoagulants early in infection may help to prevent or control disseminated intravascular coagulation. After the disease has taken hold, administration of procoagulants late in infection, is used to control hemorrhaging, to maintain oxygen levels, to manage pain. The administration of antibiotics or antimycotics are given to treat secondary infections. According to Doctors Without Borders, early treatment may increase the survival chance, since there is no known cure. Their treatment focuses on replenishing fluids, maintaining proper blood pressure, replacing lost blood, and treating related infections.

 

In late 2012, Canadian scientists discovered that the deadliest form of the virus could be transmitted by air between species. The scientists managed to prove that the virus was transmitted from pigs to monkeys without any direct contact between them, leading to fears that airborne transmission could be contributing to the wider spread of the disease in parts of Africa. Researchers from the U.S. Army Medical Research Institute of Infectious Diseases found that FDA-approved estrogen receptor drugs used to treat infertility and breast cancer (clomiphene and toremifene) inhibit the progress of Ebola virus in infected mice. Ninety percent of the mice treated with clomiphene and 50% of those treated with toremifene survived the tests. The authors of the study concluded that given their oral availability and history of human use, these drugs would be excellent candidates for repurposing efforts to treat 10) ___ virus infection in remote geographical locations, either on their own or together with other antiviral drugs. Now, human clinical trials are needed.

 

ANSWERS: 1) kidneys; 2) fluids; 3) antibodies; 4) hands; 5) prognosis; 6) bush; 7) white; 8) genetic; 9) viruses; 10) Ebola

 

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David Baltimore MD, PhD (1938-Present)

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David Baltimore: In 1975, at the age of 37, he shared the Nobel Prize for Physiology or Medicine

 

David Baltimore MD, PhD, an American virologist, university administrator, and Nobel laureate in Physiology or Medicine, is considered one of the world’s most influential biologists. He served as president of the California Institute of Technology (Caltech) from 1997 to 2006, and is currently the President Emeritus and Robert Andrews Millikan Professor of Biology at Caltech. He also served as president of Rockefeller University from 1990 to 1991, and was president of the American Association for the Advancement of Science in 2007. Dr. Baltimore has profoundly influenced international science, including key contributions to immunology, virology, cancer research, biotechnology, and recombinant DNA research, through his accomplishments as a researcher, administrator, educator, and public advocate for science and engineering. He was awarded the U.S. National Medal of Science in 1999.

 

Dr. Baltimore was born to Gertrude (Lipschitz) and Richard Baltimore in New York City. Raised in the Queens neighborhoods of Forest Hills and Rego Park, Queens, he moved with his family to suburban Great Neck, New York while he was in second grade because his mother felt that the city schools were inadequate. His father had been raised as an Orthodox Jew and his mother was an atheist. Dr. Baltimore observed Jewish holidays and would attend synagogue with his father through his Bar Mitzvah. He graduated from Great Neck High School in 1956, and credits his interest in biology to a high-school summer spent at the Jackson Laboratory’s Summer Student Program in Bar Harbor, Maine.

 

He earned a BA at Swarthmore College in 1960, and received his Ph.D. at Rockefeller University in 1964. After postdoctoral fellowships at Massachusetts Institute of Technology (MIT) and Albert Einstein College of Medicine and a non-faculty research position at the Salk Institute, he joined the MIT faculty in 1968. He was elected a Fellow of the American Academy of Arts and Sciences in 1974. In 1975, at the age of 37, he shared the Nobel Prize for Physiology or Medicine with Howard Temin and Renato Dulbecco. The citation reads, “for their discoveries concerning the interaction between tumor viruses and the genetic material of the cell.“ At the time, Baltimore’s greatest contribution to virology was his discovery of reverse transcriptase (RTase or RT). Reverse transcriptase is essential for the reproduction of retroviruses such as HIV. Working independently, Baltimore and Temin discovered reverse transcriptase, an enzyme that synthesizes DNA from RNA. Baltimore also conducted research that led to an understanding of the interaction between viruses and the genetic material of the cell. The research of all three men contributed to an understanding of the role of viruses in the development of cancer. Baltimore and Temin both studied the process by which certain tumor-causing RNA viruses (those whose genetic material is composed of RNA) replicate after they infect a cell. They simultaneously demonstrated that these RNA viruses, now called retroviruses, contain the blueprint for an unusual enzyme – a polymerase called reverse transcriptase – that copies DNA from an RNA template. The newly formed viral DNA then integrates into the infected host cell, an event that can transform the infected cell into a cancer cell.

 

In 1975, Baltimore was an organizer of the Asilomar conference on recombinant DNA. In 1982, Baltimore was appointed the founding director of MIT’s Whitehead Institute, where he remained through June 1990. In 1981, Baltimore and Vincent Racaniello, a post-doctoral fellow in his laboratory, used recombinant DNA technology to generate a plasmid encoding the genome of poliovirus, an animal RNA virus. The plasmid DNA was introduced into cultured mammalian cells and infectious poliovirus was produced. The infectious clone, DNA encoding the genome of a virus, is a standard tool used today in virology. Other important breakthroughs from Baltimore’s lab include the discovery of the transcription factor NF-?B and the recombination activating genes RAG-1 and RAG-2.

 

Baltimore became president of Rockefeller University in New York City on July 1, 1990. After resigning on December 3, 1991, Baltimore remained on the Rockefeller University faculty and continued research until spring of 1994. He then rejoined the MIT faculty.

 

Dr. Baltimore’s present research focuses on control of inflammatory and immune responses, on the roles of microRNAs in the immune system, and on the use of gene therapy methods to treat HIV and cancer in a program called “Engineering Immunity.“ He has become Director of the Joint Center for Translational Medicine, an activity that joins Caltech and UCLA in a program to translate basic science discoveries into clinical realities and where an active clinical program is under way. Baltimore has several outstanding administrative and public policy achievements to his credit. In the mid-1970s, he played an important role in creating a consensus on national science policy regarding recombinant DNA research. He served as founding director of the Whitehead Institute for Biomedical Research at MIT from 1982 until 1990. An early advocate of federal AIDS research, Baltimore co-chaired the 1986 National Academy of Sciences committee on a National Strategy for AIDS and was appointed in 1996 to head the National Institutes of Health AIDS Vaccine Research Committee.

 

Baltimore served as a member of the Independent Citizen’s Oversight Committee to the California Institute for Regenerative Medicine until 2007 and on the Board of Directors for both MedImmune until 2007 and Cellerant until 2008.He has played an important role in the development of American biotechnology since his involvement in the 1970s in the formation of Collaborative Genetics. He helped found other companies such as Calimmune and Immune Design and most recently s2A Molecular, Inc. He presently serves on the Board of Directors at several companies and non-profit institutions including the Broad Foundation and Broad Institute, and Amgen and Regulus Therapeutics. He is a member of numerous Scientific Advisory Boards, including the Broad Institute, Ragon Institute, Regulus Therapeutics, and Immune Design. He is a Scientific Partner to the venture capital firm, The Column Group, and until recently, he was a Director of the Swiss investment company BB Biotech.

 

Baltimore’s numerous honors include the 1970 Gustave Stern Award in Virology, 1971 Eli Lilly and Co. Award in Microbiology and Immunology, 1999 National Medal of Science, and 2000 Warren Alpert Foundation Prize. He was elected to the National Academy of Sciences in 1974, and is also a fellow of the American Academy of Arts and Sciences, and a foreign member of both the Royal Society of London and the French Academy of Sciences. He is past-President and Chair of the American Association of the Advancement of Science (2007-2009) and was mostly recently named a Fellow of the American Association for Cancer Research (AACR). He has published 680 peer-reviewed articles.

 

Baltimore has influenced national policy concerning recombinant DNA research and the AIDS epidemic. He has trained many doctoral students and postdoctoral fellows, several of whom have gone on to notable and distinguished research careers. Baltimore is a member of The Jackson Laboratory’s Board of Trustees, the Bulletin of the Atomic Scientists’ Board of Sponsors, the National Academy of Sciences USA (NAS), the NAS Institute of Medicine (IOM), Amgen, Inc. Board of Directors, the BB Biotech AG Board of Directors, the National Institutes of Health (NIH) AIDS Vaccine Research Committee (AVRC), and numerous other organizations and their boards.

 

Baltimore is a member of the USA Science and Engineering Festival’s Advisory Board and the Pontifical Academy of Sciences

 

During Baltimore’s tenure at Caltech, United States President Bill Clinton awarded Baltimore the National Medal of Science in 1999 for his numerous contributions to the scientific world. In 2004, Rockefeller University gave Baltimore its highest honor, Doctor of Science (honoris causa).

 

Baltimore remains the Millikan Professor of Biology at Caltech and is an active member of the Institute’s community. He is married and has one child.

 

 

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The Baltimore Classification of viruses is based on the method of viral mRNA synthesis.

 

Among huge accomplishments, David Baltimore, devised the Baltimore classification system. The ICTV classification system is used in conjunction with the Baltimore classification system in modern virus classification.

 

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