Targeting HIV's Sugar Coating: New Microbicide May Block AIDS Virus from Infecting Cells

University of Utah researchers have discovered a new class of compounds that stick to the sugary coating of the AIDS virus and inhibit it from infecting cells -- an early step toward a new treatment to prevent sexual transmission of the virus. Development and laboratory testing of the potential new microbicide to prevent human immunodeficiency virus infection is outlined in a study set for online publication in the journal Molecular Pharmaceutics. Despite years of research, there is only one effective microbicide to prevent sexual transmission of HIV, which causes AIDS, or acquired immune deficiency syndrome. Microbicide development has focused on gels and other treatments that would be applied vaginally by women, particularly in Africa and other developing regions. To establish infection, HIV must first enter the cells of a host organism and then take control of the cells' replication machinery to make copies of itself. Those HIV copies in turn infect other cells. These two steps of the HIV life cycle, known as viral entry and viral replication, each provide a potential target for anti-AIDS medicines. "Most of the anti-HIV drugs in clinical trials target the machinery involved in viral replication," says the study's senior author, Patrick F. Kiser, associate professor of bioengineering and adjunct associate professor of pharmaceutics and pharmaceutical chemistry at the University of Utah. "There is a gap in the HIV treatment pipeline for cost-effective and mass-producible viral entry inhibitors that can inactivate the virus before it has a chance to interact with target cells," he says. Kiser conducted the study with Alamelu Mahalingham, a University of Utah graduate student in pharmaceutics and pharmaceutical chemistry; Anthony Geonnotti of Duke University Medical Center in Durham, N.C.; and Jan Balzarini of Catholic University of Leuven in Belgium. The research was funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, the Catholic University of Leuven, Belgium, and the Fund for Scientific Research, also in Belgium. Synthetic Lectins Inhibit HIV from Entering Cells Lectins are a group of molecules found throughout nature that interact and bind with specific sugars. HIV is coated with sugars that help to hide it from the immune system. Previous research has shown that lectins derived from plants and bacteria inhibit the entry of HIV into cells by binding to sugars found on the envelope coating the virus. However, the cost of producing and purifying natural lectins is prohibitively high. So Kiser and his colleagues developed and evaluated the anti-HIV activity of synthetic lectins based on a compound called benzoboroxole, or BzB, which sticks to sugars found on the HIV envelope. Kiser and his colleagues found that these BzB-based lectins were capable of binding to sugar residues on HIV, but the bond was too weak to be useful. To improve binding, they developed polymers of the synthetic lectins. The polymers are larger molecules made up of repeating subunits, which contained multiple BzB binding sites. The researchers discovered that increasing the number and density of BzB binding sites on the synthetic lectins made the substances better able to bind to the AIDS virus and thus have increased antiviral activity. "The polymers we made are so active against HIV that dissolving about one sugar cube's weight of the benzoboroxole polymer in a bath tub of water would be enough to inhibit HIV infection in cells," says Kiser. Depending on the strain, HIV displays significant variations in its viral envelope, so it is important to evaluate the efficacy of any potential new treatment against many different HIV strains. Kiser and his colleagues found that their synthetic lectins not only showed similar activity across a broad spectrum of HIV strains, but also were specific to HIV and didn't affect other viruses with envelopes. The scientists also tested the anti-HIV activity of the synthetic lectins in the presence of fructose, a sugar present in semen, which could potentially compromise the activity of lectin-based drugs because it presents an alternative binding site. However, the researchers found that the antiviral activity of the synthetic lectins was fully preserved in the presence of fructose. "The characteristics of an ideal anti-HIV microbicide include potency, broad-spectrum activity, selective inhibition, mass producibility and biocompatibility," says Kiser. "These benzoboroxole-based synthetic lectins seem to meet all of those criteria and present an affordable and scalable potential intervention for preventing sexual transmission in regions where HIV is pandemic." Kiser says future research will focus on evaluating the ability of synthetic lectins to prevent HIV transmission in tissues taken from the human body, with later testing in primates. Kiser and his colleagues are also developing a gel form of the polymers, which could be used as a topical treatment for preventing sexual HIV transmission.

New Sensor Glove May Help Stroke Patients Recover Mobility

A new sensor glove may help stroke patients recover hand mobility by playing video games. 

People who have strokes are often left with moderate to severe physical impairments. Now, thanks to a glove developed at McGill, stroke patients may be able to recover hand motion by playing video games. The Biomedical Sensor Glove was developed by four final-year McGill Mechanical Engineering undergrads under the supervision of Professor Rosaire Mongrain.

It is designed to allow patients to exercise in their own homes with minimal supervision, while at the same time permitting doctors to monitor their progress from a distance, thus cutting down on hospital visits and costs.
Patients can monitor their progress thanks to software, which will generate 3D models and display them on the screen, while at the same time sending the information to the treating physician.
The glove was developed by the students in response to a design request from the startup company Jintronix Inc. The students met with company representatives once a week for several months to develop the glove, which can track the movements of the wrist, the palm and the index finger using several Inertial Measurement Units. Although similar gloves currently exist, they costs approximately $30,000. By using more accurate and less expensive sensors, the students were able to develop a glove that currently costs $1000 to produce.
Jintronix, Inc. has submitted the project to Grand Challenges Canada, which is an independent not-for-profit organization dedicated to improving the health and well-being of people in developing countries, in the hopes that they will receive funding for further development.

Oldest Fossils of Large Seaweeds, Possible Animals Tell Story About Oxygen in an Ancient Ocean

These images are part and counterpart of a macroscopic Lantian fossil, probably a seaweed, with differentiated morphologies including a distinct root-like holdfast to secure the organism on sea bottom, a conical stem, and a crown of ribbon-like structures. Scale bar is 1 centimeter. 

Almost 600 million years ago, before the rampant evolution of diverse life forms known as the Cambrian explosion, a community of seaweeds and worm-like animals lived in a quiet deep-water niche under the sea near what is now Lantian, a small village in Anhui Province of South China. Then they simply died, leaving some 3,000 nearly pristine fossils preserved between beds of black shale deposited in oxygen-free waters.

Scientists from the Chinese Academy of Sciences, Virginia Tech in the U.S., and Northwest University in Xi'an, China report the discovery of the fossils and the mystery in the Feb. 17 issue of Nature.
In addition to perhaps ancient versions of algae and worms, the Lantian biota -- named for its location -- included macrofossils with complex and puzzling structures. In all, scientists identified about 15 different species at the site.
The fossils suggest that morphological diversification of macroscopic eukaryotes -- the earliest versions of organisms with complex cell structures -- may have occurred only tens of millions of years after the snowball earth event that ended 635 million years ago, just before the Ediacaran Period. And their presence in the highly organic-rich black shale suggests that, despite the overall oxygen-free conditions, brief oxygenation of the oceans did come and go.
"So there are two questions," said Shuhai Xiao, professor of geobiology in the College of Science at Virginia Tech. "Why did this community evolve when and where it did? It is clearly different in terms of the number of species compared to biotas preserved in older rocks. There are more species here and they are more complex and larger than what evolved before. These rocks were formed shortly after the largest ice age ever, when much of the global ocean was frozen. By 635 million years ago, the snowball earth event ended and oceans were clear of ice. Perhaps that prepared the ground for the evolution of complex eukaryotes."
The team was examining the black shale rocks because, although they were laid down in waters that were not good for oxygen-dependent organisms, "they are known to be able to preserve fossils very well," said Shuhai. "In most cases, dead organisms were washed in and preserved in black shales. In this case, we discovered fossils that were preserved in pristine condition where they had lived -- some seaweeds still rooted."
The conclusion that the environment would have been poisonous is derived from geochemical data, "but the bedding surfaces where these fossils were found represent moments of geological time during which free oxygen was available and conditions were favorable. They are very brief moments to a geologist," said Xiao. "but long enough for the oxygen-demanding organisms to colonize the Lantian basin and capture the rare opportunities."
The research team suggests in the article in Nature that the Lantian basin was largely without oxygen but was punctuated by brief oxic episodes that were opportunistically populated by complex new life forms, which were subsequently killed and preserved when the oxygen disappeared. "Such brief oxic intervals demand high-resolution sampling for geochemical analysis to capture the dynamic and complex nature of oxygen history in the Ediacaran Period," said lead author Xunlai Yuan, professor of palaeontology with the Chinese Academy of Sciences.
Proving that hypothesis awaits further study. The rocks in the study region are deposited in layered beds. The nature of the rock changes subtly and there are finer and finer layers that can be recognized within each bed. "We will need to sample each layer to see whether there is any difference in oxygen contents between layers with fossils and those without" said co-author Chuanming Zhou, professor of palaeontology with the Chinese Academy of Sciences.
The research was supported by Chinese Academy of Sciences, National Natural Science Foundation of China, Chinese Ministry of Science and Technology, National Science Foundation, NASA Exobiology and Evolutionary Biology Program, and a Guggenheim fellowship to Xiao

Primates' Unique Gene Regulation Mechanism

Three baby orangutans from Tanjung Putting Orangutan Rehab Center in Borneo Indonesia. Scientists have discovered a new way genes are regulated that is unique to primates, including humans and monkeys. 

Scientists have discovered a new way genes are regulated that is unique to primates, including humans and monkeys. Though the human genome -- all the genes that an individual possesses -- was sequenced 10 years ago, greater understanding of how genes function and are regulated is needed to make advances in medicine, including changing the way we diagnose, treat and prevent a wide range of diseases.
"It's extremely valuable that we've sequenced a large bulk of the human genome, but sequence without function doesn't get us very far, which is why our finding is so important," said Lynne E. Maquat, Ph.D., lead author of the new study published February 9 in the journal Nature.
When our genes go awry, many diseases, such as cancer, Alzheimer's and cystic fibrosis can result. The study introduces a unique regulatory mechanism that could prove to be a valuable treatment target as researchers seek to manipulate gene expression -- the conversion of genetic information into proteins that make up the body and perform most life functions -- to improve human health.
The newly identified mechanism involves Alu elements, repetitive DNA elements that spread throughout the genome as primates evolved. While scientists have known about the existence of Alu elements for many years, their function, if any, was largely unknown.
Maquat discovered that Alu elements team up with molecules called long noncoding RNAs (lncRNAs) to regulate protein production. They do this by ensuring messenger RNAs (mRNAs), which take genetic instructions from DNA and use it to create proteins, stay on track and create the right number of proteins. If left unchecked, protein production can spiral out of control, leading to the proliferation or multiplication of cells, which is characteristic of diseases such as cancer.
"Previously, no one knew what Alu elements and long noncoding RNAs did, whether they were junk or if they had any purpose. Now, we've shown that they actually have important roles in regulating protein production," said Maquat, the J. Lowell Orbison Chair, professor of Biochemistry and Biophysics and director of the Center for RNA Biology at the University of Rochester Medical Center.
The expression of genes that call for the development of proteins involves numerous steps, all of which are required to occur in a precise order to achieve the appropriate timing and amount of protein production. Each of these steps is regulated, and the pathway discovered is one of only a few pathways known to regulate mRNAs directly in the midst of the protein production process.
Regulating mRNAs is one of several ways cells control gene expression, and researchers from institutions and companies around the world are honing in on this regulatory landscape in search of new ways to manage and treat disease.
According to Maquat, "This new mechanism is really a surprise. We continue to be amazed by all the different ways mRNAs can be regulated."
Maquat and the study's first author, Chenguang Gong, a graduate student in the Department of Biochemistry and Biophysics at the Medical Center, found that long noncoding RNAs and Alu elements work together to trigger a process known as SMD (Staufen 1-mediated mRNA decay). SMD conditionally destroys mRNAs after they orchestrate the production of a certain amount of proteins, preventing the creation of excessive, unwanted proteins in the body that can disrupt normal processes and initiate disease.
Specifically, long noncoding RNAs and Alu elements recruit the protein Staufen-1 to bind to numerous mRNAs. Once an mRNA finishes directing a round of protein production, Staufen-1 works with another regulatory protein previously identified by Maquat, UPF1, to initiate the degradation or decay of the mRNA so that it cannot create any more proteins.
While the research fills in a piece of the puzzle as to how our genes operate, it also accentuates the overwhelming complexity of how our DNA shapes us and the many known and unknown players involved. Maquat and Gong plan on exploring the newly identified pathway in future research.
This research was supported by a grant from the General Medical Sciences Division of the National Institutes of Health and an Elon Huntington Hooker Graduate Student Fellowship.

Portable Breast Scanner Allows Cancer Detection in the Blink of an Eye

A new portable scanner based on radio frequency technology can show in a second the presence of tumors -- malignant and benign -- in the breast on a computer. The red dot indicates the presence of a tumor.

Women could have a fast test for breast cancer and instantly identify the presence of a tumor in the comfort of their own home thanks to groundbreaking new research from the University of Manchester.
Professor Zhipeng Wu has invented a portable scanner based on radio frequency technology, which is able to show in a second the presence of tumours -- malignant and benign -- in the breast on a computer.
Using radio frequency or microwave technology for breast cancer detection has been proven by researchers in the US, Canada and UK. However, up to now, it can take a few minutes for an image to be produced, and this had to be done in a hospital or specialist care centre.
Now Professor Wu, from the University's School of Electrical and Electronic Engineering, says concerned patients can receive real-time video images in using the radio frequency scanner which would clearly and simply show the presence of a tumour.
Not only is this a quicker and less-intrusive means of testing, it also means women can be tested at GP surgeries, which could help dramatically reduce waiting times and in some cases avoid unnecessary X-ray mammography. The scanner could also be used at home for continuous monitoring of breast health.
The patented real-time radio frequency scanner uses computer tomography and works by using the same technology as a mobile phone, but with only a tiny fraction of its power.
This makes it both safe and low-cost and the electronics can be housed in a case the size of a lunch box for compactness and portability. Other existing systems are much larger.
Breast cancer is the second biggest killer in women, accounting for 8.2% of all cancer deaths. October is National Breast Cancer Awareness month.
The usual way of detecting breast cancer up to now is mammography, which works well for women over the age of 50 and can give results of up to 95% accuracy.
But it is far less effective for younger women. The detection rate could be as low as 60% for women under the age of 50, which accounts for 20% of all breast cancer cases.
At that stage it is even more important get accurate diagnosis. Early diagnosis and treatment could save thousands of lives.
The main difference between the two methods is that mammography works on density, while radio frequency technique works on dielectric contrasts between normal and diseased breast tissues.
In Professor Wu's design, as soon as the breast enters the cup an image appears on screen.
The presence of a tumour or other abnormality will show up in red as the sensor detects the difference in tissue contrasts at radio frequencies. Malignant tissues have higher permittivity and conductivity and therefore appear differently than normal ones to a screen.
Up to 30 images are generated every second, meaning a breast scan could be over in a far shorter time than they are currently.
Professor Wu said: "The system we have is portable and as soon as you lie down you can get a scan -- it's real-time.
"The real-time imaging minimises the chance of missing a breast tumour during scanning.
"Other systems also need to use a liquid or gel as a matching substance, such as in an ultrasound, to work but with our system you don't need that -- it can be done simply in oil, milk, water or even with a bra on.
"Although there is still research to be done, the system has great potential to bring a new way for breast cancer diagnosis.
"This will benefit millions of women in both developed and developing countries bearing in mind that one in nine women may develop breast cancer in their lifetime."
Professor Wu submitted his innovation of the sensor system to the IET Innovation Awards. The technology has been shortlisted in both Electronics and Measurement in Action categories. The winners will be announced in November.

Gene Therapy for Metastatic Melanoma in Mice Produces Complete Remission

A potent anti-tumor gene introduced into mice with metastatic melanoma has resulted in permanent immune reconfiguration and produced a complete remission of their cancer, according to an article to be published in the December 2010 issue of the Journal of Clinical Investigation.
Indiana University School of Medicine researchers used a modified lentivirus to introduce a potent anti-melanoma T cell receptor gene into the hematopoietic stem cells of mice. Hematopoietic stem cells are the bone marrow cells that produce all blood and immune system cells.
The T cell gene, which recognizes a specific protein found on the surface of melanoma, was isolated and cloned from a patient with melanoma. The gene-modified stems cells were then transplanted back into hosts and found to eradicate metastatic melanoma for the lifetime of the mice.
"We found that the transplantation of gene-modified hematopoietic stem cells results in a new host immune system and the complete elimination of tumor," reported Christopher E. Touloukian, M.D., an assistant professor of surgery and immunology at the IU School of Medicine and a member of the Indiana University Melvin and Bren Simon Cancer Center. "To date, cancer immunotherapies have been hampered by limited and diminishing immune responses over time. We believe this type of translational model opens new doors for patients with melanoma and potentially other cancers by taking advantage of the potent regenerative capacity of hematopoietic stem cells and new advances in gene therapy."
This research was funded by a National Institutes of Health grant.
It has paved the way for a new clinical trial in humans funded by the V Foundation for Cancer Research. The pilot phase I trial will involve treatment of 12 patients and focus primarily on the safety and efficacy of the therapy, said Dr. Touloukian, who is the senior author on the JCI paper and the principal investigator for the clinical study. The clinical trial is expected to begin accruing patients by late 2011.
In 2010, more than 68,000 patients will be diagnosed with melanoma and the disease will be associated with approximately 9,000 deaths. The state of Indiana has the 11th highest rate of melanoma incidence of all 50 states. Current treatments for metastatic melanoma, though exciting and innovative, have been highly toxic and largely unsuccessful with the most patients dying within 6 to 12 months after diagnosis.