Potential 'fountain of youth' gene found

Gene helps prevent heart attack, stroke; may offer way to block effects of aging

Date:

May 17, 2016

Source:

University of Virginia Health System

Summary:

A gene that scientific dogma insists is inactive in adults actually plays a vital role in preventing the underlying cause of most heart attacks and strokes, researchers have determined. The discovery opens a new avenue for battling those deadly conditions, and it raises the tantalizing prospect that doctors could use the gene to prevent or delay at least some of the effects of aging.

FULL STORY

---

This is an atherosclerotic lesion. Such lesions can rupture and cause heart attacks and strokes.

Credit: UVA School of Medicine

A gene that scientific dogma insists is inactive in adults actually plays a vital role in preventing the underlying cause of most heart attacks and strokes, researchers at the University of Virginia School of Medicine have determined. The discovery opens a new avenue for battling those deadly conditions, and it raises the tantalizing prospect that doctors could use the gene to prevent or delay at least some of the effects of aging.

"Finding a way to augment the expression of this gene in adult cells may have profound implications for promoting health and possibly reversing some of the detrimental effects with aging," said researcher Gary K. Owens, PhD, director of UVA's Robert M. Berne Cardiovascular Research Center.

Unexpected Protective Effect

The gene, Oct4, plays a key role in the development of all living organisms, but scientists have, until now, thought it was permanently inactivated after embryonic development. Some controversial studies have suggested it might have another function later in life, but the UVA researchers are the first to provide conclusive evidence of that: Owens and his colleagues have determined the gene plays a critical protective role during the formation of atherosclerotic plaques inside blood vessels. The rupturing of these plaques is the underlying cause of many heart attacks and strokes.

The researchers found that Oct4 controls the movement of smooth muscle cells into protective fibrous "caps" inside the plaques -- caps that make the plaques less likely to rupture. The researchers also have provided evidence that the gene promotes many changes in gene expression that are beneficial in stabilizing the plaques. This is exciting, because studies suggest that it may be possible to develop drugs or other therapeutic agents that target the Oct4 pathway as a means to reduce the incidence of heart attacks or stroke. "Our findings have major implications regarding possible novel therapeutic approaches for promoting stabilization of atherosclerotic plaques," said Olga A. Cherepanova, PhD, a senior research scientist in Owens' lab.

One surprising finding from UVA's research: When the researchers blocked the effect of Oct4 in mice, they thought the atherosclerotic plaques might become smaller, because of the reduced number of smooth muscle cells inside. Instead, the plaques grew larger, less stable and more dangerous, stuffed with lipids, dead cells and other damaging components.

Advancing Regenerative Medicine

While UVA's research has focused on how Oct4 offers cardiovascular protection, Owens and his colleagues believe the gene could also prove critical to the field of regenerative medicine, which investigates the growth and replacement of tissues and organs. The researchers believe that Oct4 and its family of target genes are activated in other somatic cells -- the non-reproductive cells in the body -- and play a key role in the cells' ability to repair damage and heal wounds. Studies to test this are under way in Owens' lab.

Oct4 is one of the "stem cell pluripotency factors" described by Shinya Yamanaka, MD, PhD, for which he received the 2012 Nobel Prize. His lab and many others have shown that artificial over-expression of Oct4 within somatic cells grown in a lab dish is essential for reprogramming these cells into induced pluripotential stem cells, which can then develop into any cell type in the body or even an entire organism.

The UVA researchers suspect that at least some of the detrimental effects of aging, including the increased possibility of a plaque rupture, stem from a decrease in the body's ability to reactivate Oct4. "Finding a way to reactivate this pathway may have profound implications for health and aging," Owens said. "We think this is just the tip of the iceberg for controlling plasticity of somatic cells, and this could impact many human diseases and the field of regenerative medicine. Who knows, this may end up being the 'fountain-of-youth gene,' a way to revitalize old and worn-out cells. Only time will tell."

---

Story Source:

The above post is reprinted from materials provided by University of Virginia Health System. Note: Materials may be edited for content and length.

---

Journal Reference:

1. Olga A Cherepanova, Delphine Gomez, Laura S Shankman, Pamela Swiatlowska, Jason Williams, Olga F Sarmento, Gabriel F Alencar, Daniel L Hess, Melissa H Bevard, Elizabeth S Greene, Meera Murgai, Stephen D Turner, Yong-Jian Geng, Stefan Bekiranov, Jessica J Connelly, Alexey Tomilin, Gary K Owens. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nature Medicine, 2016; DOI:10.1038/nm.4109

Read More

Predicting the spread of the Zika virus

The risk is given as the percentage of observing local transmission by the end of 2016, colored by intensity (0-15, 15-30, 30-45 and 45-60 percent, respectively). The origin country Brazil and countries that have already experienced case importation prior to importation event in Brazil are colored by grey.

Credit: Hiroshi HISHIURA

A new tool by Japan-based researchers predicts the risk of Zika virus importation and local transmission for 189 countries.

Countries that are well connected to/from Brazil have been at particularly high risk of importation, according to the analysis by a team of researchers from the University of Tokyo, Hokkaido University, and the Japan Science and Technology Agency.

However, subtropical and tropical countries with a history of dengue and other mosquito-borne diseases have the greatest risk of the virus spreading once it arrives in the country. This means many nations in South and Central America, as well as the Caribbean, face the highest risk of infection and should take measures to prevent mosquito bites, according to the study that was recently published in Peer J. France, southern parts of China and the United Arab Emirates also fall into this category having experienced previous outbreaks.

"We have shown that the predicted risk of local transmission was frequently seen in tropical and subtropical countries with dengue or chikungunya epidemic experience, while the risk of importation was more scattered around the world," said Hiroshi Nishiura, a professor of hygiene at Hokkaido University.

The Zika virus was first found in Uganda in 1947, and then detected in 39 countries around the world, including the United States, India and Japan. In early 2015, a Zika virus outbreak in Brazil was soon followed by a high number of microcephaly cases, in which babies are born with abnormally small heads. The link between the two is not definitively understood, but is strongly suspected. Since the Brazil outbreak, Zika virus has been detected in an additional 39 countries, including in Europe, the U.K., South America and Asia.

Many researchers are working to anticipate the virus's potential spread, especially given that it can be carried by lightly infected travelers and then passed onto others by mosquitos. Global concern and attention are elevated with thousands of visitors set to attend the Olympics in Rio de Janeiro this summer.

Professor Nishiura and his colleagues predicted the virus' potential of importation and local transmission by the end of 2016 using a survival analysis model, information about airline transportation networks, and transmission data for dengue and chikungunya viruses, which are also transmitted by the same mosquito species. They collected Zika data up to January 31, 2016, and they note that new cases were confirmed in more countries shortly thereafter.

The authors recommend that a finer scale analysis be done to more accurately predict the spread within regions. For example, models should incorporate ecological information about mosquitoes.

"Despite a clear need to improve predictions in the future, the present study successfully devised a simple global risk prediction of importation and local transmission," Prof. Nishiura said. "Countries at low risk may focus on prevention among pregnant women who must travel to epidemic areas."

---

Story Source:

The above post is reprinted from materials provided by Hokkaido University. Note: Materials may be edited for content and length.

---

Journal Reference:

1. Kyeongah Nah, Kenji Mizumoto, Yuichiro Miyamatsu, Yohei Yasuda, Ryo Kinoshita, Hiroshi Nishiura. Estimating risks of importation and local transmission of Zika virus infection. PeerJ, 2016; 4: e1904 DOI:10.7717/peerj.1904

Read More

Fighting cancer with the help of someone else's immune cells

Date:

May 19, 2016

Source:

Netherlands Cancer Institute

Summary:

A new step in cancer immunotherapy: researchers show that even if one's own immune cells cannot recognize and fight their tumors, someone else's immune cells might.

FULL STORY

---

A human T-cell.

Credit: NIH

A new step in cancer immunotherapy: researchers from the Netherlands Cancer Institute and University of Oslo/Oslo University Hospital show that even if one's own immune cells cannot recognize and fight their tumors, someone else's immune cells might. Their proof of principle study is published in the journal Science on May 19th.

The study shows that adding mutated DNA from cancer cells into immune stimulating cells from healthy donors create an immune response in the healthy immune cells. Inserting the targeted components from the donor immune cells back into the immune cells of the cancer patients, the researchers were able to make cancer patients' own immune cells recognize cancer cells.

The extremely rapidly developing field of cancer immunotherapy aims to create technologies that help the body's own immune system to fight cancer. There are a number of possible causes that can prevent the immune system from controlling cancer cells. First, the activity of immune cells is controlled by many 'brakes' that can interfere with their function, and therapies that inactivate these brakes are now being tested in many human cancers. As a second reason, in some patients the immune system may not recognize the cancer cells as aberrant in the first place. As such, helping the immune system to better recognize cancer cells is one of the main focuses in cancer immunotherapy.

Ton Schumacher of the Netherlands Cancer Institute and Johanna Olweus of the University of Oslo and Oslo University Hospital decided to test whether a 'borrowed immune system' could "see" the cancer cells of the patient as aberrant. The recognition of aberrant cells is carried out by immune cells called T cells. All T cells in our body scan the surface of other cells, including cancer cells, to check whether they display any protein fragments on their surface that should not be there. Upon recognition of such foreign protein fragments, T cells kill the aberrant cells. As cancer cells harbor faulty proteins, they can also display foreign protein fragments -- also known as neo-antigens -- on their surface, much in the way virus-infected cells express fragments of viral proteins.

To address whether the T cells of a patient react to all the foreign protein fragments on cancer cells, the research teams first mapped all possible neo-antigens on the surface of melanoma cells from three different patients. In all 3 patients, the cancer cells seemed to display a large number of different neo-antigens. But when the researchers tried to match these to the T cells derived from within the patient's tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.

Next, they tested whether the same neo-antigens could be seen by T-cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neo-antigens that had not been seen by the patients' T cells.

"In a way, our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens.," says Ton Schumacher. "The receptor that is used by these donor T-cells can then be used to genetically modify the patient's own T cells so these will be able to detect the cancer cells."

"Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput. We are currently exploring high-throughput methods to identify the neo-antigens that the T cells can "see" on the cancer and isolate the responding cells. But the results showing that we can obtain cancer-specific immunity from the blood of healthy individuals are already very promising," says Johanna Olweus.

This research was performed within the K.G.Jebsen Center for Cancer Immunotherapy, at the University of Oslo/ Oslo University Hospital and The Netherlands Cancer Institute.

---

Story Source:

The above post is reprinted from materials provided by Netherlands Cancer Institute. Note: Materials may be edited for content and length.

---

Journal Reference:

1. E. Stronen, M. Toebes, S. Kelderman, M. M. van Buuren, W. Yang, N. van Rooij, M. Donia, M.-L. Boschen, F. Lund-Johansen, J. Olweus, T. N. Schumacher. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science, 2016; DOI: 10.1126/science.aaf2288

Source: Science Daily

Read More

Antibody therapy opens door to potential new treatment for HIV

The development of antiretroviral therapy, a combination of drugs that slows the replication of HIV in the body, has transformed the treatment of this infection. What was once a certain death sentence is now a chronic condition that people can live with for decades.

But this therapy has drawbacks. There are side effects, including kidney problems, decreased bone density, and gastrointestinal problems. And if a person discontinues his or her treatment, even missing a few doses, the level of the virus in the body is able to rebound quickly.

Researchers from The Rockefeller University, along with collaborators from the University of Cologne, are developing a new kind of treatment, an antibody-based drug that may provide a better strategy for long-term control of HIV. Recent findings from a Phase 1 clinical trial, published on May 5 inScience, offer new insights about how the antibody functions.

"This study provides evidence that a single dose of an antibody stimulates patients' immune response, enabling them to make new or better antibodies against the virus," explains Till Schoofs, a postdoctoral fellow and one of the study's first authors. Schoofs is a member of the Laboratory of Molecular Immunology, led by Michel Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman Professor, who is the study's senior author.

"We reported last year that this treatment can greatly reduce the amount of virus that's present in someone's blood," Dr. Schoofs adds, "but we wanted to follow the patients for a longer period of time to study how their immune systems were adapting to the new therapy."

Neutralizing a deadly virus

The molecule used in the research, 3BNC117, is called a broadly neutralizing antibody because it has the ability to fight a wide range of HIV strains. Johannes Scheid, a student in Nussenzweig's lab, isolated it several years ago from an HIV-infected patient whose immune system had an exceptional ability to neutralize HIV in the blood by preventing the virus from infecting and destroying a specific type of immune cells, called CD4 cells, in patients. The destruction of CD4 cells is a hallmark of AIDS.

Early studies showed that 3BNC117 can neutralize more than 80 percent of HIV strains that are found around the world. The investigators therefore theorized that giving the antibody to patients would help them to fight the virus as well.

The clinical trial included 15 patients who had high levels of the virus in their blood, and 12 other patients whose virus levels were being controlled with antiretroviral therapy (ART). The majority of trial participants were treated at The Rockefeller University Hospital. The patients were infused with a single dose of 3BNC117 and were monitored over a six-month period.

The investigators found that 14 out of 15 patients who had high levels of the virus at the time they were given the antibody were making new antibodies that were able to neutralize a number of different strains of HIV.

"It usually takes several years for the body to begin to make good antibodies against HIV," Schoofs says. "So there might be an even better effect later on, especially if patients are given more than one dose of 3BNC117."

The next steps in this research are to test 3BNC117 in combination with other antibodies that target HIV, to determine whether an even stronger antiviral effect can be found. The researchers are also conducting a Phase 2 trial in which patients receiving ART are switched to antibody treatment.

Exploring an antibody's function

In a companion study published in the same issue of Science, the investigators wanted to determine what further benefits treatment with 3BNC117 may have over ART.

They looked at the results of the clinical trial, and used a mathematical model of HIV dynamics to predict how the patients' levels of HIV would have fared if 3BNC117 did nothing else than to neutralize HIV in the blood and block new infection. Their analysis showed that neutralization of the virus alone doesn't explain the steep drop in the virus levels observed in patients--leading the scientists to suspect that there must be another component to the antibody's efficacy.

Working in a mouse model, the researchers saw evidence that 3BNC117 was able to engage the animals' immune cells and accelerate their clearance of HIV-infected cells. "This shows that the antibody not only can exert pressure on the virus, but also can shorten the survival of infected cells," says first author Ching-Lan Lu, a visiting student in Dr. Nussenzweig's lab. "Our results explain why post-exposure prophylaxis"--short-term treatment after exposure to HIV to reduce infection--"with antibodies is more effective than ART in our mouse models."

In addition, they could potentially make it possible to address a major obstacle to curing HIV: the virus's ability to establish a latent reservoir soon after infection, and so hide out in the body and evade treatment. A follow-up clinical study is currently underway at Rockefeller to assess whether offering antibody drugs to patients receiving ART can help reduce or alter their HIV reservoirs.

Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.

Journal References:

T. Schoofs, F. Klein, M. Braunschweig, E. F. Kreider, A. Feldmann, L. Nogueira, T. Oliveira, J. C. C. Lorenzi, E. H. Parrish, G. H. Learn, A. P. West, P. J. Bjorkman, S. J. Schlesinger, M. S. Seaman, J. Czartoski, M. J. McElrath, N. Pfeifer, B. H. Hahn, M. Caskey, M. C. Nussenzweig.HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science, 2016; DOI: 10.1126/science.aaf0972

C.-L. Lu, D. K. Murakowski, S. Bournazos, T. Schoofs, D. Sarkar, A. Halper-Stromberg, J. A. Horwitz, L. Nogueira, J. Golijanin, A. Gazumyan, J. V. Ravetch, M. Caskey, A. K. Chakraborty, M. C. Nussenzweig.Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science, 2016; DOI: 10.1126/science.aaf1279

Read More

Gut feeling: Research examines link between stomach bacteria, PTSD

Dr. John Bienenstock (left) and Dr. Paul Forsythe in their lab. The researchers are studying whether bacteria in the gut can be used to cure or prevent neurological conditions such as post-traumatic stress disorder (PTSD), anxiety or depression. (Photo courtesy of Dr. John Bienenstock and Dr. Paul Forsythe)

Could bacteria in your gut be used to cure or prevent neurological conditions such as post-traumatic stress disorder (PTSD), anxiety or even depression? Two researchers sponsored by the Office of Naval Research (ONR) think that's a strong possibility.

Dr. John Bienenstock and Dr. Paul Forsythe--who work in The Brain-Body Institute at McMaster University in Ontario, Canada--are investigating intestinal bacteria and their effect on the human brain and mood.

"This is extremely important work for U.S. warfighters because it suggests that gut microbes play a strong role in the body's response to stressful situations, as well as in who might be susceptible to conditions like PTSD," said Dr. Linda Chrisey, a program officer in ONR's Warfighter Performance Department, which sponsors the research.

The trillions of microbes in the intestinal tract, collectively known as the gut microbiome, profoundly impact human biology--digesting food, regulating the immune system and even transmitting signals to the brain that alter mood and behavior. ONR is supporting research that's anticipated to increase warfighters' mental and physical resilience in situations involving dietary changes, sleep loss or disrupted circadian rhythms from shifting time zones or living in submarines.

Through research on laboratory mice, Bienenstock and Forsythe have shown that gut bacteria seriously affect mood and demeanor. They also were able to control the moods of anxious mice by feeding them healthy microbes from fecal material collected from calm mice.

Bienenstock and Forsythe used a "social defeat" scenario in which smaller mice were exposed to larger, more aggressive ones for a couple of minutes daily for 10 consecutive days. The smaller mice showed signs of heightened anxiety and stress--nervous shaking, diminished appetite and less social interaction with other mice. The researchers then collected fecal samples from the stressed mice and compared them to those from calm mice.

"What we found was an imbalance in the gut microbiota of the stressed mice," said Forsythe. "There was less diversity in the types of bacteria present. The gut and bowels are a very complex ecology. The less diversity, the greater disruption to the body."

Bienenstock and Forsythe then fed the stressed mice the same probiotics (live bacteria) found in the calm mice and examined the new fecal samples. Through magnetic resonance spectroscopy (MRS), a non-invasive analytical technique using powerful MRI technology, they also studied changes in brain chemistry.

"Not only did the behavior of the mice improve dramatically with the probiotic treatment," said Bienenstock, "but it continued to get better for several weeks afterward. Also, the MRS technology enabled us to see certain chemical biomarkers in the brain when the mice were stressed and when they were taking the probiotics."

Both researchers said stress biomarkers could potentially indicate if someone is suffering from PTSD or risks developing it, allowing for treatment or prevention with probiotics and antibiotics.

Later this year, Bienenstock and Forsythe will perform experiments involving fecal transplants from calm mice to stressed mice. They also hope to secure funding to conduct clinical trials to administer probiotics to human volunteers and use MRS to monitor brain reactions to different stress levels.

Gut microbiology is part of ONR's program in warfighter performance. ONR also is looking at the use of synthetic biology to enhance the gut microbiome. Synthetic biology creates or re-engineers microbes or other organisms to perform specific tasks like improving health and physical performance. The field was identified as a top ONR priority because of its potential far-ranging impact on warfighter performance and fleet capabilities.

Story Source:

The above story is based on materials provided by Office of Naval Research. Note: Materials may be edited for content and length.

Journal Reference:

S. Leclercq, P. Forsythe, J. Bienenstock.Posttraumatic Stress Disorder: Does the Gut Microbiome Hold the Key? The Canadian Journal of Psychiatry, 2016; 61 (4): 204 DOI: 10.1177/0706743716635535

Read More

Regenerating brain tissue brings hope for a new treatment against Alzheimer's and Parkinson’s

Researchers developed a nanogel that enables the growth of new neurons.

Working with animal models, researchers were able to cross the electroencephalic barrier, introduce a nanogel and achieve the growth of neurons within the gel, which shows that it is possible to promote regeneration of brain tissue.

After six years of research with materials engineering and bioengineering, the first nanogel for neuron growth is at the experimental stage and could be applied as a treatment for neurodegenerative diseases such as Alzheimer's and Parkinson in addition to its use during brain scans, like nuclear magnetic resonance or CAT scans, to improve the visibility of the brain.

Dr. Victor Castaño, from the Centre of Applied Physics and Advanced Technology (CFATA) of the National University of Mexico (UNAM) explained that the nanogel is a biocompatible material, functional within the human body that when injected into the brain and through external excitation it allows the spontaneous growth of neurons.

"We wanted to improve and advance the generation of biomaterials for regenerating brain tissue. During the experiments we crossed the electroencephalic barrier that keeps the brain isolated from the body; by crossing it, we were allowed to introduce the nanogel and for it to act without harming the body. We watched how, within the gel, neurons began to grow; this wouldn't have been possible in any other way.

"Also, with the help of lase tweezers we took two light phases and stimulated the neuron as if we were pulling it and putting it to exercise, this gave us favorable results in increased neuronal tissue," explained Dr. Castaño, member of the Commission of Biomedical Specialty, from the Engineering Academy of Mexico (AIM).

After laboratory modeling and use of the right materials, the work team composed of researchers from the Institute of Neurobiology at UNAM and the University of Singapore created a small gelatin made with nanoparticles.

"The ability to offer alternatives to diseases that currently don't have a cure and it being with Mexican technology has great impact and is of great value; however, we must work in a transdisciplinary way to allow scientific and technological advances," concluded the Mexican researcher.

Story Source:

The above story is based on materials provided by Investigación y Desarrollo. Note: Materials may be edited for content and length.

Read More

Moving, electrically 'silent' source initiates brain waves

Finding may help in understanding memory formation, treating epilepsy

Date:

April 20, 2016

Source:

Case Western Reserve University

Summary:

A traveling spike generator appears to move across the hippocampus and change direction while generating brain waves. The generator itself, however, produces no electrical signal. The speed of the waves most closely match those found in epilepsy and in healthy sleep and theta waves.

 

FULL STORY

---

Artist's rendering of neurons (stock image).

Credit: © fotoliaxrender / Fotolia

Brain waves that spread through the hippocampus are initiated by a method not seen before -- a possible step toward understanding and treating epilepsy, according to researchers at Case Western Reserve University.

The researchers discovered a traveling spike generator that appears to move across the hippocampus -- a part of the brain mainly associated with memory -- and change direction, while generating brain waves. The generator itself, however, produces no electrical signal.
"In epilepsy, we've thought the focus of seizures is fixed and, in severe cases, that part of the brain is surgically removed," said Dominique Durand, Elmer Lincoln Lindseth Professor in Biomedical Engineering at Case School of Engineering and leader of the study. "But if the focus, or source, of seizures moves -- as we've described -- that's problematic."
The findings, in the Journal of Neuroscience, builds on Durand's work published late last year, identifying brain waves that appear to be spread through a mild electrical field -- not the known transmissions through synapses, diffusion or gap junctions.
The speed of the waves most closely match those found in epilepsy and in healthy sleep and theta waves, which are thought to help form memories.
On this latest study, Durand worked with PhD students Mingming Zhang, Rajat S. Shivacharan, postdoctoral researcher Chia-Chu Chiang, and research associate Luis E. Gonzales-Reyes.
Source Search
Working from the same data that revealed the brain waves, the team found the source was also moving too slow for synaptic transmission and a little too fast for diffusion.
"We don't know what's causing the propagation," Durand said.
The engineers estimate the size of the source is 300 to 500 micrometers in diameter. It appears to generate spikes all around its periphery, but the source moves nearly 100 times slower than the spikes.
"The source is like a moving car with pulsing lights," Durand said.
To find the source of the waves, the team tracked spikes propagating through an unfolded rat hippocampus. They used a penetrating microelectrode array of 64 electrodes arranged in a grid on the tissue, to record the activity.
The delay between the initial spike and the peaks recorded along consecutive electrodes in the grid was measured in milliseconds.
By inserting time values surrounding those recorded by each of the electrodes, the researchers refined the grid to include a total of 256 points or pixels.
Using this data, the researchers created an isochrone map -- a map of lines connecting locations where a given spike arrived at the same time. The maps look something like topographical maps, but instead of showing elevations, the lines show the wave fronts as they spread over time.
The source of each wave propagation was estimated to be the geometric center of the electrodes that recorded the first neural firing at maximum amplitude.
Each brain wave appeared to have a slew of sources, firing it along either from the temporal region toward the septal or vice versa.
The team applied Doppler effect equations to the frequency of spikes in front and behind the source. Like the direct observations, the results strongly indicate the sources are moving smoothly across the hippocampus.
When a source reached the hippocampus edge, it started in the opposite direction, which may explain observations by others that waves moving in opposite directions have been found in the same brain tissue at the same time.
Digging deeper
Durand's lab is trying to understand how a source that moves without diffusion can move without electricity and generate electrical spikes.
The team is also trying to understand what these non-synaptic events do and whether they are relevant to processing neural activity. Because the speed of these waves is close to the speed of sleep and theta waves, the researchers speculate they may be involved in consolidating memory.
If the phenomenon is relevant to epilepsy, it may provide a target for therapies. "Can we block the spikes without blocking the source?" Durand asked.
The lab is now developing new neural imaging methods to better track sources and learn how they propagate spikes.

---

Story Source:
The above post is reprinted from materials provided by Case Western Reserve University. Note: Materials may be edited for content and length.

---

Journal Reference:

1. M. Zhang, R. S. Shivacharan, C.-C. Chiang, L. E. Gonzalez-Reyes, D. M. Durand. Propagating Neural Source Revealed by Doppler Shift of Population Spiking Frequency. Journal of Neuroscience, 2016; 36 (12): 3495 DOI: 10.1523/JNEUROSCI.3525-15.2016

---

Read More

New Microbes expands tree of life

Bacteria make up nearly two-thirds of all biodiversity on Earth, half of them uncultivable

This is a new and expanded view of the tree of life, with clusters of bacteria (left), uncultivable bacteria called 'candidate phyla radiation' (center, purple) and, at lower right, the Archaea and eukaryotes (green), including humans.

Credit: Graphic by Zosia Rostomian, Lawrence Berkeley National Laboratory

The tree of life, which depicts how life has evolved and diversified on the planet, is getting a lot more complicated.

Researchers at the University of California, Berkeley, who have discovered more than 1,000 new types of bacteria and Archaea over the past 15 years lurking in Earth's nooks and crannies, have dramatically rejiggered the tree to account for these microscopic new life forms.

"The tree of life is one of the most important organizing principles in biology," said Jill Banfield, a UC Berkeley professor of earth and planetary science and environmental science, policy and management. "The new depiction will be of use not only to biologists who study microbial ecology, but also biochemists searching for novel genes and researchers studying evolution and earth history."

Much of this microbial diversity remained hidden until the genome revolution allowed researchers like Banfield to search directly for their genomes in the environment, rather than trying to culture them in a lab dish. Many of the microbes cannot be isolated and cultured because they cannot live on their own: they must beg, borrow or steal stuff from other animals or microbes, either as parasites, symbiotic organisms or scavengers.

The new tree, to be published online April 11 in the new journal Nature Microbiology, reinforces once again that the life we see around us -- plants, animals, humans and other so-called eukaryotes -- represent a tiny percentage of the world's biodiversity.

"Bacteria and Archaea from major lineages completely lacking isolated representatives comprise the majority of life's diversity," said Banfield, who also has an appointment at Lawrence Berkeley National Laboratory. "This is the first three-domain genome-based tree to incorporate these uncultivable organisms, and it reveals the vast scope of as yet little-known lineages."

According to first author Laura Hug, a former UC Berkeley postdoctoral fellow who is now on the biology faculty at the University of Waterloo in Ontario, Canada, the more than 1,000 newly reported organisms appearing on the revised tree are from a range of environments, including a hot spring in Yellowstone National Park, a salt flat in Chile's Atacama desert, terrestrial and wetland sediments, a sparkling water geyser, meadow soil and the inside of a dolphin's mouth. All of these newly recognized organisms are known only from their genomes.

"What became really apparent on the tree is that so much of the diversity is coming from lineages for which we really only have genome sequences," she said. "We don't have laboratory access to them, we have only their blueprints and their metabolic potential from their genome sequences. This is telling, in terms of how we think about the diversity of life on Earth, and what we think we know about microbiology."

One striking aspect of the new tree of life is that a group of bacteria described as the "candidate phyla radiation" forms a very major branch. Only recognized recently, and seemingly comprised only of bacteria with symbiotic lifestyles, the candidate phyla radiation now appears to contain around half of all bacterial evolutionary diversity.

While the relationship between Archaea and eukaryotes remains uncertain, it's clear that "this new rendering of the tree offers a new perspective on the history of life," Banfield said.

"This incredible diversity means that there are a mind-boggling number of organisms that we are just beginning to explore the inner workings of that could change our understanding of biology," said co-author Brett Baker, formerly of Banfield's UC Berkeley lab but now at the University of Texas, Austin, Marine Science Institute.

Tree depicts life we see today

Charles Darwin first sketched a tree of life in 1837 as he sought ways of showing how plants, animals and bacteria are related to one another. The idea took root in the 19th century, with the tips of the twigs representing life on Earth today, while the branches connecting them to the trunk implied evolutionary relationships among these creatures. A branch that divides into two twigs near the tips of the tree implies that these organisms have a recent common ancestor, while a forking branch close to the trunk implies an evolutionary split in the distant past.

Archaea were first added in 1977 after work showing that they are distinctly different from bacteria, though they are single-celled like bacteria. A tree published in 1990 by microbiologist Carl Woese was "a transformative visualization of the tree," Banfield said. With its three domains, it remains the most recognizable today.

With the increasing ease of DNA sequencing in the 2000s, Banfield and others began sequencing whole communities of organisms at once and picking out the individual groups based on their genes alone. This metagenomic sequencing revealed whole new groups of bacteria and Archaea, many of them from extreme environments, such as the toxic puddles in abandoned mines, the dirt under toxic waste sites and the human gut. Some of these had been detected before, but nothing was known about them because they wouldn't survive when isolated in a lab dish.

For the new paper, Banfield and Hug teamed up with more than a dozen other researchers who have sequenced new microbial species, gathering 1,011 previously unpublished genomes to add to already known genome sequences of organisms representing the major families of life on Earth.

She and her team constructed a tree based on 16 separate genes that code for proteins in the cellular machine called a ribosome, which translates RNA into proteins. They included a total of 3,083 organisms, one from each genus for which fully or almost fully sequenced genomes were available.

The analysis, representing the total diversity among all sequenced genomes, produced a tree with branches dominated by bacteria, especially by uncultivated bacteria. A second view of the tree grouped organisms by their evolutionary distance from one another rather than current taxonomic definitions, making clear that about one-third of all biodiversity comes from bacteria, one-third from uncultivable bacteria and a bit less than one-third from Archaea and eukaryotes.

"The two main take-home points I see in this tree are the prominence of major lineages that have no cultivable representatives, and the great diversity in the bacterial domain, most importantly, the prominence of candidate phyla radiation," Banfield said. "The candidate phyla radiation has as much diversity within it as the rest of the bacteria combined."

---

Story Source:

The above post is reprinted from materials provided by University of California - Berkeley. The original item was written by Robert Sanders.Note: Materials may be edited for content and length.

---

Journal Reference:

1. Laura A. Hug, Brett J. Baker, Karthik Anantharaman, Christopher T. Brown, Alexander J. Probst, Cindy J. Castelle, Cristina N. Butterfield, Alex W. Hernsdorf, Yuki Amano, Kotaro Ise, Yohey Suzuki, Natasha Dudek, David A. Relman, Kari M. Finstad, Ronald Amundson, Brian C. Thomas, Jillian F. Banfield. A new view of the tree of life. Nature Microbiology, 2016; 16048 DOI: 10.1038/nmicrobiol.2016.48

Date:

April 11, 2016

Source:

University of California - Berkeley

Read More

Why neural stem cells may be vulnerable to Zika infection

This image shows a section through a stem cell-derived cerebral organoid (mini-brain in a dish) where the radial glia stem cells are shown in red, neurons are in blue, and the AXL receptors are in green. (Elizabeth Di Lullo)

Zika's hypothesized attraction to human neural stem cells may come from its ability to hijack a protein found on the surface of these cells, using it as an entryway to infection. In Cell Stem Cellon March 30, researchers at the University of California, San Francisco show that the AXL surface receptor, normally involved in cell division, is highly abundant on the surface of neural stem cells, but not on neurons in the developing brain.

The neural stem cells that express AXL are only present during the second trimester of pregnancy. These cells, called radial glial cells, give rise to the variety of cell types (e.g., neurons and astrocytes) that help build the cerebral cortex. The researchers also found AXL expressed by the stem cells of the retina. Disruption of this range of cell types is consistent with the multiple symptoms associated with Zika infection in the developing fetus--including microcephaly, a brain lacking in folds, and eye lesions.

"While by no means a full explanation, we believe that the expression of AXL by these cell types is an important clue for how the Zika virus is able to produce such devastating cases of microcephaly, and it fits very nicely with the evidence that's available," says senior study author Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. "AXL isn't the only receptor that's been linked with Zika infection, so next we need to move from 'guilt by association' and demonstrate that blocking this specific receptor can prevent infection."

Kriegstein's lab has a long-time interest in brain development. When the Zika outbreak hit, first authors Tomasz Nowakowski and Alex Pollen realized from previous studies that viruses similar to Zika--such as Dengue virus--seem to use AXL as an entry point to infection. They then used gene expression analysis (single-cell RNA sequencing) to look for AXL's presence across different cell types in mouse brain, ferret brain, human stem cell-derived brain organoids, and developing brain tissue in humans. Each of the models showed expression of AXL by the radial glial cells.

The researchers then used antibody trackers (immunohistochemistry) in the developing tissues and organoids to find out where the AXL receptor was most likely to be found on the neural stem cells. They found that AXL aggregates toward areas where the neural progenitors come into contact with either cerebrospinal fluid or blood vessels. This unique position would give a virus such as Zika an easy way to reach a vulnerable population of host cells.

"We still don't understand why Zika in particular is so virulent to the developing brain," Kriegstein says. "It could be that the virus travels more easily though the placental-fetal barrier or that the virus enters cells more readily than related infections."

Pending confirmation that Zika is using AXL for neural stem cell entry, the Kriegstein group is interested in exploring if the receptor could be exploited for therapeutic purposes. Since the protein is important for neural stem cell proliferation, it is unlikely that blocking AXL will be an option in the fetal brain. But perhaps there's a way to treat women at risk with an AXL inhibitor to stop Zika getting into the developing fetus in the first place.

This research was supported by the National Institutes of Health and the Damon Runyon Cancer Research Foundation.

Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.

Journal Reference:

Nowakowski et al. Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor. Cell Stem Cell, 2016 DOI: 10.1016/j.stem.2016.03.012

Read More

Ancient Viruses Lurking in Our DNA

Do You Really Think that your DNA is all human? Think again.

A new discovery suggests that it's even less human than scientists thought.

Nineteen newly found pieces of non-human DNA – which were left by viruses infected our ancestors over hundreds and thousands of years ago – Those Links have just been found, lurking in between our very own genes.

And one stretch of newfound DNA, found in about 50 of the 2,500 people studied, contains an intact, full genetic recipe for an entire virus, say the scientists who published their findings in the Proceedings of the National Academy of Sciences.

Whether or not it can replicate, or reproduce, it isn't yet known. But other studies of ancient virus DNA have shown it can affect the humans who carry it.

In addition to finding these new stretches, the scientists also confirmed 17 other pieces of virus DNA found in human genomes by other scientists in recent years.

The study looked at the entire span of DNA, or genome, from people from around the world, including a large number from Africa -- where the ancestors of modern humans originated before migrating around the world. The team used sophisticated techniques to compare key areas of each person's genome to the "reference" human genome.

Working at Tufts University and the University of Michigan Medical School, the researchers made the findings with funding from the National Institutes of Health.

HERV-enly find

The findings add to what science already knows about human endogenous retroviruses, or HERVs. That's the name for the ancient infectious viruses that inserted a DNA-based copy of their own RNA genetic material into our ancestors' genomes. They're part of the same type of virus that includes the modern human immunodeficiency virus, which causes AIDS.

Over generations, the virus-generated DNA kept getting copied and handed down when humans reproduced. That's how it ended up in our DNA today. In fact, about 8 percent of what we think of as our "human" DNA actually came from viruses. In some cases, HERV sequences have been adopted by the human body to serve a useful purpose, such as one that helps pregnant women's bodies build a cell layer around a developing fetus to protect it from toxins in the mother's blood.

The new HERVs are part of the family called HERV-K. The intact whole viral genome, or provirus, just found was on the X chromosome; it's been dubbed Xq21. It's only the second intact provirus found to be hiding in human DNA.

In the researchers' own words: "This one looks like it is capable of making infectious virus, which would be very exciting if true, as it would allow us to study a viral epidemic that took place long ago," says senior author and virologist John Coffin, Ph.D. of the Tufts University School of Medicine. "This research provides important information necessary for understanding how retroviruses and humans have evolved together in relatively recent times."

"Many studies have tried to link these endogenous viral elements to cancer and other diseases, but a major difficulty has been that we haven't actually found all of them yet," says co-first author Zachary H. Williams, a Ph.D. student at the Sackler School of Graduate Biomedical Sciences at Tufts University in Boston. "A lot of the most interesting elements are only found in a small percentage of people, which means you have to screen a large number of people to find them."

"This is a thrilling discovery," says co-first author Julia Wildschutte, Ph.D., who began the work as a Ph.D. student in Coffin's lab at Tufts. "It will open up many doors to research. What's more, we have confirmed in this paper that we can use genomic data from multiple individuals compared to the reference human genome to detect new HERVs. But this has also shown us that some people carry insertions that we can't map back to the reference."

U-M genetics researcher Jeffrey Kidd, Ph.D., worked with Wildschutte when she was a member of his laboratory team. "These are remnants of ancient events that have not been fixed in the population as a whole, but rather happened in the ancestors of some people alive today," Kidd says. "There have been a number of examples of other HERVs that insert themselves next to human genes or near them, and have impact on their expression. We're interested in applying these methods to find other types of viral or mobile element insertions."

Genetic teamwork

The Michigan team used methods for characterizing repetitive DNA sequences that Kidd and his team had developed, while Coffin and Williams used complementary techniques. Wildschutte is now at Bowling Green State University.

Many of the genomes they examined were from the 1000 Genomes Project, an international collaboration. Another set of genomes came from work Kidd and colleagues at Stanford University had done as part of the Human Genome Diversity Project, with a focus on DNA samples from African volunteers.

These latter samples showed more signs of HERVs, in line with the high level of genetic diversity in African populations. That diversity stems from the longtime stability and intermixing of the continent's population -- as opposed to other populations in Europe, Asia and the Americas that stem from specific out-migrations in ancient times.

Cataloging all the HERV insertions in humans will require even more scanning of whole human genomes, which are becoming easier to come by as technology improves and becomes less expensive. And although intact proviruses lurking in our DNA may be rare, the impact of other HERV sequences on our health or disease is probably not.

The research was funded by the National Institutes of Health (OD009154, CA089441, GM112339) as well as the American Cancer Society and the F.M. Kirby Foundation.

---

Story Source:

The above post is reprinted from materials provided by University of Michigan Health System. Note: Materials may be edited for content and length.

---

Journal Reference:

1.    Julia Halo Wildschutte, Zachary H. Williams, Meagan Montesion, Ravi P. Subramanian, Jeffrey M. Kidd, John M. Coffin. Discovery of unfixed endogenous retrovirus insertions in diverse human populations.Proceedings of the National Academy of Sciences, 2016; 201602336 DOI: 10.1073/pnas.1602336113

Read More

Why are women more prone to knee injuries than men?

Researchers from The University of Texas Medical Branch at Galveston have found that women who take the birth control pill, which lessen and stabilize estrogen levels, were less likely to suffer serious knee injuries. The findings are currently available inMedicine & Science in Sports & Exercise, the official journal of the American College of Sports Medicine.

Female athletes are 1.5 to 2 times more likely than their male counterparts to injure their anterior cruciate ligament, or ACL. The ACL is a ligament that connects the top and bottom portions of the knee. Damage to this ligament is a serious athletic injury that can be career altering. Return-to-play rates after ACL injury are as low as 49 percent among soccer players. Also, this injury may lead to lifelong issues with knee instability, altered walking gait and early onset arthritis.

Using a national insurance claims and prescription database of 23,428 young women between 15 and 19, the study found that women with an ACL knee injury who were taking the birth control pill were less likely to need corrective surgery than women of the same age with ACL injuries who do not use the birth control pill.

Researchers have proposed that the female hormone estrogen makes women more vulnerable to ACL injury by weakening this ligament. A previous investigation found that more ACL injuries in women occur during the points of their menstrual cycle when estrogen levels are high.

"Birth control pills help maintain lower and more consistent levels of estrogen, which may prevent periodic ACL weakness," said lead author and M.D. -- Ph.D. student Aaron Gray. "With this in mind, we examined whether oral contraceptive use protected against ACL injuries that require surgery in women."

Women between15-19 y in need of ACL reconstructive surgery, the age group with the highest rates of ACL injuries by a wide margin, were 22 percent less likely to be using the birth control pill than non-injured women of the same age.

Gray said that puberty might explain the high number of ACL injury cases in young women of this age. During puberty, there is a sharp rise in estrogen levels as well as growth spurts in the legs. Following one of these growth spurts, it takes time for the adolescent to develop good coordination with their newly elongated limbs.

"Young athletes currently use birth control pills for various reasons including more predictable cycles and lighter periods," Gray said. "Injury risk reduction could potentially be added to that list with further, prospective investigations."

Story Source:

The above story is based on materials provided by University of Texas Medical Branch at Galveston. Note: Materials may be edited for content and length.

Journal Reference:

Aaron M Gray, Zbgniew Gugala, Jacques G Baillargeon. Effects of Oral Contraceptive Use on Anterior Cruciate Ligament Injury Epidemiology. Medicine & Science in Sports & Exercise, 2015; 1 DOI: 10.1249/MSS.0000000000000806

Read More

Turn mortal enemies into allies? Ants can

Ants (stock image). Ants are also aggressive toward each other, fighting to the death over their tree territories. While the consequences for losing colonies are stark -- loss of territory or colony death -- Rudolph and UF postdoctoral research associate Jay McEntee wanted to understand the costs to the winners. (© ttshutter / Fotolia)

On an African plateau surrounded by flat-topped trees as far as the eye could see, wind whistled through the acacia thorns like someone blowing across a bottle. Kathleen Rudolph was more concerned with the ants raining down on her from the trees. The hat, long sleeves and garden gloves the University of Florida researcher wore for protection didn't help.

The acacia ants she studies, Crematogaster mimosae, use their fearsome bite to defend their host trees against large animals such as elephants and giraffes that eat the trees' leaves. Even elephants' thick skin can't protect them from the ants, which bite them inside their trunks.

"They really seem to have a knack for finding your soft tissue," Rudolph said. "It's a nasty business."

Ants are also aggressive toward each other, fighting to the death over their tree territories. While the consequences for losing colonies are stark -- loss of territory or colony death -- Rudolph and UF postdoctoral research associate Jay McEntee wanted to understand the costs to the winners.

After a fight, victorious colonies have to defend their newly gained territory with a workforce heavily depleted by fighting. In a new study funded in part by a National Geographic Society/Waitt Fund Grant and published in Behavioral Ecology, Rudolph and McEntee found that victorious colonies might offset this challenge by recruiting members of the losing colonies to help.

In experiments based at Mpala Research Centre in Kenya, researchers instigated ant wars by tying unrelated colonies' trees together, counting casualties in tarps placed below. By simulating the browsing of a large mammal, they discovered that victorious colonies are less able to defend their host trees after fights. After analyzing the DNA of nearly 800 ants, they discovered that fighting changes the genetic make-up of victorious colonies.

Long viewed as fortresses of cooperating sisters, where relatives of the queen work for her benefit, Rudolph's work demonstrates that non-relatives can become part of the colony -- and potentially defend its residents and territory.

Researchers were further surprised to find that, in some cases, fatal fights with thousands of casualties do not produce a distinct winner. Instead, colonies cease fighting and fuse together, with the queen of each colony still alive.

"Colonies are battling so aggressively that many individuals die, but then they are able to just stop fighting and form a lasting truce," Rudolph said. "It's pretty remarkable."

How they know to stop fighting remains is a mystery, showing the need for research on recognition systems. One possibility, Rudolph says, is that fighting changes the odors ants use to distinguish nestmates from potential invaders.

"If so, the updated or blended cues shared by prior foes may help end aggressive responses," Rudolph said.

Sorting out these processes could contribute to our understanding of an intriguing aspect of physical conflict -- that animal combatants become more similar biologically through combat. That can be true for humans, too: A 2013 study showed that the skin bacteria communities of competing roller derby teams converge during bouts, not unlike Rudolph's findings in ants.

"Physical combat not only yields biological winners and losers," Rudolph said. "It can alter the identity of its combatants."

Story Source:

The above story is based on materials provided by University of Florida. Note: Materials may be edited for content and length.

Journal Reference:

Kathleen P. Rudolph, Jay P. McEntee.Spoils of war and peace: enemy adoption and queen-right colony fusion follow costly intraspecific conflict in acacia ants. Behavioral Ecology, 2015; arv219 DOI: 10.1093/beheco/arv219

Read More