A multidisciplinary research group at UCLA has now teamed up to not only visualize a virus but to use the results to adapt the virus so that it can deliver medication instead of disease.

In a paper published in the journal Science, Hongrong Liu, a UCLA postdoctoral researcher in microbiology, immunology and molecular genetics, and colleagues reveal an atomically accurate structure of the adenovirus that shows the interactions among its protein networks. The work provides critical structural information for researchers around the world attempting to modify the adenovirus for use in vaccine and gene-therapy treatments for cancer.

To modify a virus for gene therapy, researchers remove its disease-causing DNA, replace it with medications and use the virus shell, which has been optimized by millions of years of evolution, as a delivery vehicle.

Lily Wu, a UCLA professor of molecular and medical pharmacology and co-lead author of the study, and her group have been attempting to manipulate the adenovirus for use in gene therapy, but the lack of information about receptors on the virus’s surface had hampered their quest.

“We are engineering viruses to deliver gene therapy for prostate and breast cancers, but previous microscopy techniques were unable to visualize the adapted viruses,” Wu said. “This was like trying to a piece together the components of a car in the dark, where the only way to see if you did it correctly was to try and turn the car on.”

To better visualize the virus, Wu sought assistance from Hong Zhou, a UCLA professor of microbiology, immunology and molecular genetics and the study’s other lead author. Zhou uses cryo-electron microscopy (cryoEM) to produce atomically accurate three-dimensional models of biological samples such as viruses.

Wu, who is also a researcher at the California NanoSystems Institute (CNSI) at UCLA, learned of Zhou’s work after he was jointly recruited to UCLA from the University of Texas Medical School at Houston by the UCLA Department of Microbiology, Immunology and Molecular Genetics and UCLA’s CNSI.

About a year ago, once the transfer of Zhou’s lab was complete, Sok Boon Koh, one of Wu’s students, sought out Zhou’s group for their expertise and initiated the collaboration.

“This project exemplifies my excitement about being part of an institute as innovative as CNSI,” Zhou said. “Not only am I able to work with state-of-the-art equipment, but because CNSI is the hub for nanotechnology research and commercialization at UCLA, I have the opportunity to collaborate with colleagues across many disciplines.”

Working in the Electron Imaging Center for Nanomachines at the CNSI, a lab run by Zhou, the researchers used cryoEM to create a 3-D reconstruction of the human adenovirus from 31,815 individual particle images.

“Because the reconstruction reveals details up to a resolution of 3.6 angstroms, we are able to build an atomic model of the entire virus, showing precisely how the viral proteins all fit together and interact,” Zhou said. An angstrom is the distance between the two hydrogen atoms in a water molecule, and the entire adenovirus is about 920 angstroms in diameter.

Armed with this new understanding, Wu and her group are now moving forward with their engineered versions of adenovirus to use for gene therapy treatment of cancer.

“This breakthrough is a great leap forward, but there are still many obstacles to overcome,” Wu said. “If our work is successful, this therapy could be used to treat most forms of cancer, but our initial efforts have focused on prostate and breast cancers because those are the two most common forms of cancer in men and women, respectively.”

The group is working with the adenovirus because previous research has established it as a good candidate for gene therapy due to its efficiency in delivering genetic materials inside the body. The virus shell is also a safe delivery vehicle; tests have shown that the shell does not cause cancer, a problem encountered with some other virus shells. The adenovirus is relatively non-pathogenic naturally, causing only temporary respiratory illness in 5 to 10 percent of people.

CryoEM enables such a high-resolution reconstruction of biological structures because samples, in water, are imaged directly. In contrast, with X-ray crystallography (the conventional technique for atomic resolution models of biological structures), researchers grow crystal structures replicating the sample and then use diffraction to solve the crystal structure. This technique is limited because it is difficult to grow crystals for all proteins, samples for x-ray crystallography need to be very pure and uniform, and crystals of large complexes may not diffract to high resolution. These limitations resulted in critical areas of the adenovirus surface being unresolved using x-ray crystallography.

From The Secret Daily Teachings by Rhonda Byrne

Because liver cells (hepatocytes) cannot be grown in the laboratory, researching liver disorders is extremely difficult. However, today’s new research, which was funded by the Wellcome Trust and the Medical Research Council (MRC), demonstrates how to create diseased liver-like cells from patients suffering from a variety of liver disorders.

By replicating the organ’s cells, researchers can not only investigate exactly what is happening in a diseased cell, they can also test the effectiveness of new therapies to treat these conditions. It is hoped that their discovery will lead to tailored treatments for specific individuals and eventually cell-based therapy — when cells from patients with genetic diseases are ‘cured’ and transplanted back. Additionally, as the process could be used to model cells from other parts of the body, their findings could have implications for conditions affecting other organs.

Dr Ludovic Vallier of the MRC Centre for Stem Cell Biology and Regenerative Medicine, University of Cambridge, principal investigator of the research, said: “Our work represents an important step towards delivering the clinical promises of stem cells. However, more work remains to be done and our group is dedicated to achieving this ultimate goal by increasing the knowledge necessary for the development of new therapies.”

In the UK, liver disease is the fifth largest cause of death after cardiovascular, cancer, stroke, and respiratory diseases. Over the past 30 years mortality from liver disease in young and middle-aged people has increased over six times, with the number of individuals dying from the disease increasing at a rate of 8-10 per cent every year.

By 2012, the UK is expected to have the highest liver disease death rates in Europe and, without action to tackle the disease, it could overtake stroke and coronary heart disease as the leading cause of death within the next 10-20 years. In the United States, it accounts for approximately 25,000 deaths a year.

For their research, the scientists took skin biopsies from seven patients who suffered from a variety of inherited liver diseases and three healthy individuals (the control group). They then reprogrammed cells from the skin samples back into stem cells. These stem cells were then used to generate liver cells which mimicked a broad range of liver diseases — the first time patient-specific liver diseases have been modelled using stem cells — and to create ‘healthy’ liver cells from the control group. Importantly, the three diseases the scientists modelled covered a diverse range of pathological mechanisms, thereby demonstrating the potential application of their research on a wide variety of disorders.

Dr Tamir Rashid of the Laboratory for Regenerative Medicine, University of Cambridge, lead author of the paper, said: “We know that given the shortage of donor liver organs alternative strategies must urgently be sought. Our study improves the possibility that such alternatives will be found — either using new drugs or a cell-based therapeutic approach.”

Professor Mark Thursz, a specialist in liver disease and Professor of Hepatology at Imperial College (who was not affiliated with the study), commented on the importance of the research: “Liver disease is the fifth most common cause of mortality in many developed countries and unlike the other leading causes of death, the rate of liver related mortality is increasing.

“The development of patient specific liver cell lines from stem cells is a significant advance in the battle against liver diseases. This technology holds promise in the short term by providing new tools to explore the biology of liver diseases and in the long term as a potential source of liver cells for patients with liver failure.”

Scientists described advances toward these drugs Aug. 23 during a special symposium, “Drugging the Undruggable,” at the 240th National Meeting of the American Chemical Society. The advances could lead to a new generation of medicines for treating cancer, diabetes, and other major diseases, they said.

In one advance, scientists reported on a new family of potential drugs that are capable of blocking a key protein that’s involved in the development of cancer. Called “stapled peptides,” the substances get their name from chemical “braces” that hold the peptides, or protein fragments, in a compact shape that gives them high stability in comparison to their unfolded versions. The three-dimensional shape is critical for the peptide to function normally and help orchestrate body processes. The chemical stapling allows them to resist destruction by enzymes, easily penetrate cells, and bind to biochemical machinery within cells.

Their report indicated that the stapled peptides prevented the growth of cancer cells in a group of test animals, a key advance toward the start of clinical trials in a group of cancer patients.

“Stapled peptides represent an entirely new class of potential drugs,” said study leader Gregory Verdine, Ph.D., who has been studying the molecules for the past decade and helped pioneer their development. “They herald a new era in the drug-discovery world.”

There are hundreds of thousands of proteins in the human body, many of them with links to human disease. However, only a tiny fraction — about 20 percent — of these proteins is considered “druggable.” Thanks to a new generation of drug discovery technologies, that tiny fraction is now on the rise.

“The entire pharmaceutical industry has been working on drug-design platforms that focus on this little sliver of human drug targets and this limits the drug arsenal available to doctors,” said Verdine, a chemical biologist at Harvard University in Cambridge, Mass. “What’s required is an entirely new class of drugs that overcome the shortcomings of drugs of the past.”

In addition to “stapled peptides,” scientists described new insights into how proteins interact with other proteins, the use of small molecules to target and treat cancer, and related topics. The presenters included scientists from government, industry, and academia.

You should be sincere in figuring out what drives you the most in your life. What is the reason of your dissatisfaction? Why you want to be above others?

1. Inferiority feeling
2. Delight in control
3. Ambitions and status/fame seeking
4. Retaliation to the people in power or society as a whole
5. Retaliation to  certain people
6. Compassion and sense of justice
7. Striving for a better life
8. Excessive libido
9. Creative drive

Be honest! You are not trying to cheat yourself, aren’t you?

1. I don’t know what I really want
2. Lack of planning
3. Bad priorities setting
4. Overreacting on external signals, getting distracted from your current task
5. Can’t see the results, that is why don’t believe in success

Those who REALLY want to succeed MUST constantly and diligently improve his/her skills.

Seminars, trainings, books, classes, podcasts, webinars, news – whatever it takes to advance your personality. Step by step, no fake excuses and procrastinations. Every day, hour, second and whatever the weather is outside.

Every time I awake at the mornings I feel some disappointment on what my life is. It seemed just yesterday like I had very positive mindset and where all that is now. Damn it.

How to be what some call “infatigable worker”?

“This study establishes the real potential for using iPS cells in cardiac treatment,” says Timothy Nelson, M.D., Ph.D., first author on the Mayo Clinic study. “Bioengineered fibroblasts acquired the capacity to repair and regenerate infarcted hearts.”

This is the first application of iPS-based technology for heart disease therapy. Previously iPS cells have been used on only three other disease models: Parkinson’s disease, sickle cell anemia and hemophilia A. The ultimate goal is to use iPS cells derived from patients to repair injury. Using a person’s own cells in the process eliminates the risk of rejection and the need for anti-rejection drugs. One day this regenerative medicine strategy may alleviate the demand for organ transplantation limited by donor shortage, the researchers say.

“This iPS innovation lays the groundwork for translational applications,” comments Andre Terzic, M.D., Ph.D., Mayo Clinic physician -scientist and senior author. “Through advances in nuclear reprogramming, we should be able to reverse the fate of adult cells and customize ‘on demand’ cardiovascular regenerative medicine.”

The Mayo Clinic team genetically reprogrammed fibroblasts via a “stemness-related” human gene set to dedifferentiate into an iPS cell capable of then redifferentiating into new heart muscle. When transplanted into damaged mouse hearts, iPS cells engrafted after two weeks, and after four weeks significantly contributed to improved structure and function of the damaged heart, in contrast to ineffective ordinary fibroblasts.

Compared to non-engineered fibroblasts, the iPS cells:

• Restored heart muscle performance lost after the heart attack
• Stopped progression of structural damage in the damaged heart
• Regenerated tissue at the site of heart damage

ScienceDaily (July 21, 2009)